Nitrogen-containing aromatic derivatives

ABSTRACT

Compounds represented by the following general formula: 
                         
[wherein A g  is an optionally substituted 5- to 14-membered heterocyclic group, etc.; X g  is —O—, —S—, etc.; Y g  is an optionally substituted C 6-14  aryl group, an optionally substituted 5- to 14-membered heterocyclic group, etc.; and T g1  is a group represented by the following general formula:
 
                         
(wherein E g  is a single bond or —N(R g2 )—, R g1  and R g2  each independently represent a hydrogen atom, an optionally substituted C 1-6  alkyl group, etc. and Z g  represents a C 1-8  alkyl group, a C 3-8  alicyclic hydrocarbon group, a C 6-14  aryl group, etc.)],
 
salts thereof or hydrates of the foregoing.

RELATED APPLICATIONS

This is a divisional of Ser. No. 11/293,785 filed on Dec. 2, 2005 U.S.Pat. No. 7,612,092, which is a divisional of Ser. No. 10/420,466 filedon Apr. 18, 2003 U.S. Pat. No. 7,253,286, which is acontinuation-in-part application of application serial no.PCT/JP01/09221 filed on Oct. 19, 2001.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to novel compounds which are effective forprevention and treatment of various diseases associated with abnormalangiogenesis, and to medical compositions such as angiogenesisinhibitors and antitumor agents comprising the novel compounds.

2. Related Background of the Invention

Angiogenesis is an essential biological phenomenon for fetal vascularformation and morphological and functional development of organs. Newblood vessels are assembled through several processes includingendothelial cell migration, proliferation and tube formation, and theparticipation of mast cells, lymphocytes, interstitial cells and thelike has been shown to be important in this process (J. Folkman and Y.Shing, J. Biol. Chem., 267, 10931, 1992). In adult individuals,physiological angiogenesis occurs during the female estrous cycle, butpathological increase in angiogenesis in adult individuals is known tobe connected with onset or progression of various diseases. Specificdiseases associated with abnormal angiogenesis include cancer,rheumatoid arthritis, atherosclerosis, diabetic retinopathy, angioma,psoriasis, and the like (J. Folkman, N. Engl. J. Med., 333, 1757, 1995).In particular, the literature has indicated angiogenesis dependency forsolid tumor growth, and angiogenesis inhibitors are therefore promisingas new therapeutic agents for intractable solid tumors (J. Folkman, J.Natl. Cancer Inst., 82, 4, 1990).

The prior art includes compounds based on a urea structure, described inWO99/00357 and WO00/43366. WO99/00357 mentions biphenylurea derivativeswhich have an inhibiting action on raf kinase and an antitumor effect,but their angiogenesis-inhibiting effect is not disclosed. WO00/43366describes quinoline derivatives and quinazoline derivatives whichexhibit a weak karyomorphism-altering effect on A375 human melanomacells in vitro and an antiproliferative effect on endothelial cellsstimulated by vascular epithelial growth factor (VEGF), and which thushave an antitumor effect, but their effect on angiogenic factors otherthan VEGF is not disclosed.

SUMMARY OF THE INVENTION

As mentioned above, it is ardently desired to provideangiogenesis-inhibiting compounds which are useful as drugs. However,clinically effective compounds that exhibit excellentangiogenesis-inhibiting effects and high usefulness as medicines havenot yet been discovered.

It is an object of the present invention to investigate and discoverangiogenesis-inhibiting compounds which (1) exhibit antitumor activitythrough a powerful angiogenesis-inhibiting effect or a powerfulangiogenesis-inhibiting and cancer cells growth-inhibiting effect, (2)are highly useful as drug materials in terms of their properties,biokinetics and safety, and (3) are useful for amelioration, preventionand treatment of various diseases associated with abnormal increase inangiogenesis.

As a result of much diligent research in light of the circumstancesdescribed above, the present inventors have succeeded in synthesizingnovel compounds represented by the following general formula (I) andtheir salts or hydrates, and have completed the present invention upondiscovering that the compounds of general formula (I) and their salts orhydrates exhibit an excellent angiogenesis-inhibiting effect.

Specifically, the invention relates to:

-   <1> a compound represented by the following general formula:

[wherein A^(g) is an optionally substituted C₆₋₁₄ aryl group or anoptionally substituted 5- to 14-membered heterocyclic group; X^(g) is asingle bond, —O—, —S—, a C₁₋₆ alkylene group, —SO—, —SO₂— or —N(R^(g3))—(wherein R^(g3) is a hydrogen atom, an optionally substituted C₁₋₆ alkylgroup or an optionally substituted C₂₋₇ acyl group); Y^(g) is anoptionally substituted C₆₋₁₄ aryl group, an optionally substituted 5- to14-membered heterocyclic group, an optionally substituted C₁₋₈ alkylgroup, an optionally substituted C₃₋₈ alicyclic hydrocarbon group, anoptionally substituted C₆₋₁₄ aryl-C₁₋₆ alkyl group, an optionallysubstituted 5- to 14-membered heteroaryl-C₁₋₆ alkyl group,—(CH₂)_(g)SO₂— (wherein g is an integer of 1 to 8),—(CH₂)_(fa)—CH═CH—(CH₂)_(fb)— (wherein fa and fb each represent 0, 1, 2or 3), —(CH₂)_(fa)—CH═CH—(CH₂)_(fb)—SO₂— (wherein fa and fb eachrepresent 0, 1, 2 or 3), —(CH₂)_(fa)—C≡C—(CH₂)_(fb)— (wherein fa and fbeach represent 0, 1, 2 or 3) or —(CH₂)_(fa)—C≡C—(CH₂)_(fb)—SO₂— (whereinfa and fb each represent 0, 1, 2 or 3); and T^(g1) is (1) a grouprepresented by the following general formula:

{wherein E^(g) is a single bond or —N(R^(g2))— (wherein R^(g2) is ahydrogen atom, an optionally substituted C₁₋₆ alkyl group, an optionallysubstituted C₂₋₆ alkenyl group, an optionally substituted C₂₋₆ alkynylgroup, an optionally substituted C₃₋₈ alicyclic hydrocarbon group, anoptionally substituted C₂₋₇ acyl group or an optionally substituted C₂₋₇alkoxycarbonyl group); R^(g1) is a hydrogen atom, an optionallysubstituted C₁₋₆ alkyl group, an optionally substituted C₂₋₆ alkenylgroup, an optionally substituted C₂₋₆ alkynyl group, an optionallysubstituted C₃₋₈ alicyclic hydrocarbon group, an optionally substitutedC₂₋₇ acyl group or an optionally substituted C₂₋₇ alkoxycarbonyl group;and Z^(g) is a hydrogen atom, an optionally substituted C₁₋₈ alkylgroup, an optionally substituted C₂₋₆ alkenyl group, an optionallysubstituted C₂₋₆ alkynyl group, an optionally substituted C₃₋₈ alicyclichydrocarbon group, an optionally substituted C₆₋₁₄ aryl group, anoptionally substituted C₆₋₁₄ aryl-C₁₋₆ alkyl group, —OR²⁰⁰, —SR²⁰⁰,—COR²⁰⁰, —SO₂R²⁰⁰ (wherein R²⁰⁰ is a hydrogen atom, an optionallysubstituted C₁₋₈ alkyl group, an optionally substituted C₃₋₈ alicyclichydrocarbon group, an optionally substituted C₆₋₁₄ aryl group, anoptionally substituted C₆₋₁₄ aryl-C₁₋₆ alkyl group, an optionallysubstituted 5- to 14-membered heterocyclic group or an optionallysubstituted 5- to 14-membered heterocyclic-C₁₋₆ alkyl group), anoptionally substituted 5- to 14-membered heterocyclic group or anoptionally substituted 5- to 14-membered heterocyclic-C₁₋₆ alkyl group},or (2) a group represented by the following general formula:

{wherein R^(g1) and Z^(g) have the same definitions as R^(g1) and Z^(g)above; and Z^(g1) and Z^(g2) may be the same or different and each is(1) a single bond, (2) an optionally oxo-substituted C₁₋₆ alkylene groupalso optionally having one or more atoms selected from —O—, —S— and anitrogen atom within or at the end of the chain, or (3) an optionallysubstituted C₂₋₆ alkenyl group}], a salt thereof or a hydrate of theforegoing;

-   <2> a compound represented by the following general formula:

[wherein A is an optionally substituted 5- to 14-membered aromaticheterocyclic group; X is an oxygen atom, a sulfur atom, —SO— or —SO₂; Yis an optionally substituted C₆₋₁₄ aryl group, an optionally substituted5- to 14-membered aromatic heterocyclic group or an optionallysubstituted C₁₋₆ alkylene group; E is a single bond or —NR²—; R¹ and R²are each independently a hydrogen atom, an optionally substituted C₁₋₆alkyl group, an optionally substituted C₂₋₆ alkenyl group, an optionallysubstituted C₂₋₆ alkynyl group, an optionally substituted C₃₋₈ alicyclichydrocarbon group, an optionally substituted C₂₋₇ acyl group or anoptionally substituted C₂₋₇ alkoxycarbonyl group; and Z is a grouprepresented by the formula —Z¹¹—Z¹² (wherein Z¹¹ is a single bond, anoxygen atom, a sulfur atom, —CO—, —SO₂— or an optionally substitutedC₁₋₆ alkylene group and Z¹² is a hydrogen atom, an optionallysubstituted C₁₋₆ alkyl group, an optionally substituted C₂₋₆ alkenylgroup, an optionally substituted C₂₋₆ alkynyl group, an optionallysubstituted C₃₋₈ alicyclic hydrocarbon group, an optionally substitutedC₆₋₁₄ aryl group, an optionally substituted 5- to 14-memberedheterocyclic group, an optionally substituted 5- to 14-membered aromaticheterocyclic group or a group represented by the formula:

(wherein Z³¹, Z³³ and Z³⁴ are each independently a methylene group,—CO—, —NH— or —O—, and Z³² is a single bond, a methylene group, —CO—,—NH— or —O—)), with the proviso that A may be an optionally substitutedwith 1 to 6 groups, each selected from the group consisting of (1) acyano group, (2) a halogen atom, (3) a nitro group and (4) the formula—V^(X1)—V^(X2)—V^(X22)—V^(X3) (wherein V^(X1), V^(X2) and V^(X22) areeach independently a single bond, an oxygen atom, a sulfur atom, —CO—,—SO—, —SO₂—, —NR^(X1)—, —CONR^(X1)—, —NR^(X1)CO—, —SO₂NR^(X1)—,—NR^(X1)SO₂—, —O—CO—, —C(O)O—, —NR^(X1)C(O)O—, —NR^(X1)C(O)NR^(X2)—,—O—C(O)NR^(X1)—, —O—C(O)O—, an optionally substituted C₁₋₆ alkylenegroup, an optionally substituted C₂₋₆ alkenyl group, an optionallysubstituted C₂₋₆ alkynyl group, an optionally substituted C₃₋₈ alicyclichydrocarbon group, an optionally substituted C₆₋₁₄ aryl group, anoptionally substituted 5- to 14-membered heterocyclic group or anoptionally substituted 5- to 14-membered aromatic heterocyclic group;and V^(X3), R^(X1) and R^(X2) are each independently a hydrogen atom, anoptionally substituted C₁₋₆ alkyl group, an optionally substituted C₂₋₆alkenyl group, an optionally substituted C₂₋₆ alkynyl group, anoptionally substituted C₃₋₈ alicyclic hydrocarbon group, an optionallysubstituted C₆₋₁₄ aryl group, an optionally substituted 5- to14-membered heterocyclic group, an optionally substituted 5- to14-membered aromatic heterocyclic group or an optionally substitutedC₁₋₆ alkoxy group)1, a salt thereof or a hydrate of the foregoing;

-   <3> a compound according to <2>, a salt of the compound or a hydrate    of the foregoing, wherein X is an oxygen atom or a sulfur atom;-   <4> a compound according to <2> or <3>, a salt of the compound or a    hydrate of the foregoing, wherein Z is an optionally substituted    cyclopropyl group, an optionally substituted 2-thiazolyl group or a    group represented by the formula:

(wherein Z¹³ is a nitrile group, a methylsulfonyl group or a —NHCOCH₃group);

-   <5> a compound according to any one of <2> to <4>, a salt of the    compound or a hydrate of the foregoing, wherein E is a group    represented by the formula —NR²— (wherein R² has the same definition    as R² in <2>), and Y is an optionally substituted phenyl group, an    optionally substituted pyridyl group or a group represented by the    formula:

(wherein W¹¹ and W¹² are each independently an optionally substitutedcarbon atom or a nitrogen atom);

-   <6> a compound according to any one of <2> to <4>, a salt of the    compound or a hydrate of the foregoing, wherein E is a single bond,    and Y is a further optionally substituted group represented by the    formula:

(wherein W¹³ is an optionally substituted carbon atom or a nitrogenatom);

-   <7> a compound according to any one of <2> to <6>, a salt of the    compound or a hydrate of the foregoing, wherein A is a group    represented by the formula:

[wherein W is an optionally substituted carbon atom or a nitrogen atom;R^(a13) is a hydrogen atom, a halogen atom, an optionally substitutedC₁₋₆ alkyl group, an optionally substituted C₁₋₆ alkoxy group, an aminogroup or a nitro group; R^(a12) is a cyano group or a group representedby the formula:

(wherein V^(a11) is —CO— or —SO₂—; and V^(a12), V^(a13), and V^(a14) areeach independently a hydrogen atom, an optionally substituted C₁₋₆ alkylgroup, an optionally substituted C₂₋₆ alkenyl group, an optionallysubstituted C₂₋₆ alkynyl group, an optionally substituted C₃₋₈ alicyclichydrocarbon group, an optionally substituted C₆₋₁₄ aryl group, anoptionally substituted 5- to 14-membered heterocyclic group or anoptionally substituted 5- to 14-membered aromatic heterocyclic group);and R^(a11) is a group represented by the formula—V^(a21)—V^(a22)—V^(a23) (wherein V^(a21) is an optionally substitutedC₁₋₆ alkylene group, a single bond or a group represented by theformula:

V^(a22) is a single bond, an oxygen atom, a sulfur atom, —CO—, —SO—,—SO₂—, —CONR^(a14)—, —SO₂NR^(a14)—, —NR^(a14)SO₂—, —NR^(a14)CO— or—NR^(a14)— (wherein R^(a14) is a hydrogen atom, an optionallysubstituted C₁₋₆ alkyl group or an optionally substituted C₃₋₈ alicyclichydrocarbon group); and V^(a23) is a hydrogen atom, an optionallysubstituted C₁₋₆ alkyl group, an optionally substituted C₂₋₆ alkenylgroup, an optionally substituted C₂₋₆ alkynyl group, an optionallysubstituted C₃₋₈ alicyclic hydrocarbon group, an optionally substitutedC₆₋₁₄ aryl group, an optionally substituted 5- to 14-memberedheterocyclic group or an optionally substituted 5- to 14-memberedaromatic heterocyclic group)];

-   <8> a compound according to any one of <2> to <6>, a salt of the    compound or a hydrate of the foregoing, wherein A is a group    represented by the formula:

(wherein W is an optionally substituted carbon or a nitrogen atom; andR^(a11), R^(a12) and R^(a13) have the same definitions as R^(a11),R^(a12) and R^(a13) in <7>);

-   <9> a compound according to any one of <2> to <6>, a salt of the    compound or a hydrate of the foregoing, wherein A is a further    optionally substituted group represented by the formula:

[wherein W is an optionally substituted carbon atom or a nitrogen atom;and A^(b11) is (1) an optionally substituted 5- to 14-memberedheterocyclic group or (2) a group represented by the formula:

(wherein V^(b11) and V^(b12) are each independently a single bond,—SO₂—, —NHCO— or a group represented by the formula —(CH₂)_(b)—CO—(wherein b is an integer of 0 to 6); R^(b13) is a single bond, anoptionally substituted C₁₋₆ alkylene group, an optionally substitutedC₃₋₈ alicyclic hydrocarbon group or an optionally substituted 5- to14-membered heterocyclic group; and R^(b11) and R^(b12) are eachindependently a hydrogen atom, a hydroxyl group, a halogen atom, anoptionally substituted C₁₋₆ alkyl group, an optionally substituted C₂₋₆alkenyl group, an optionally substituted C₂₋₆ alkynyl group, anoptionally substituted C₃₋₈ alicyclic hydrocarbon group, an optionallysubstituted C₆₋₁₄ aryl group, an optionally substituted 5- to14-membered aromatic heterocyclic group or an optionally substituted 5-to 14-membered heterocyclic group)];

-   <10> a compound according to any one of <2> to <6>, a salt of the    compound or a hydrate of the foregoing, wherein A is a group    represented by the formula:

[wherein W is an optionally substituted carbon or a nitrogen atom;R^(c13) is (1) a hydrogen atom, (2) a cyano group, (3) a halogen atom,(4) a formyl group, (5) an optionally substituted C₂₋₆ alkyl group, (6)a group represented by the formula:

(wherein V^(c21) is —CO— or a methylene group; V^(c22) and V^(c23) areeach independently a hydrogen atom, an optionally substituted C₁₋₆ alkylgroup, an optionally substituted C₂₋₆ alkenyl group, an optionallysubstituted C₂₋₆ alkynyl group, an optionally substituted C₃₋₈ alicyclichydrocarbon group, an optionally substituted 5- to 14-memberedheterocyclic group, an optionally substituted 5- to 14-membered aromaticheterocyclic group or an optionally substituted C₆₋₁₄ aryl group), or(7) a group represented by the formula —V^(c2)—O—V^(c22) (whereinV^(c21) and V^(c22) have the same definitions as V^(c21) and V^(c22)above); R^(c12) is a hydrogen atom, an optionally substituted C₁₋₆ alkylgroup or an optionally substituted C₃₋₈ alicyclic hydrocarbon group; andR^(c11) is a group represented by the formula —V^(c11)—V^(c12)—V^(c13)(wherein V^(c11) is a single bond, an oxygen atom, an optionallysubstituted benzene ring, an optionally substituted 5- to 14-memberedaromatic heterocyclic group or —CO—; V^(c12) is a single bond, an oxygenatom or an optionally substituted C₁₋₆ alkylene group; and V^(c13) is(1) an optionally substituted C₁₋₆ alkyl group, (2) an optionallysubstituted C₂₋₆ alkenyl group, (3) an optionally substituted C₂₋₆alkynyl group, (4) an optionally substituted C₃₋₈ alicyclic hydrocarbongroup, (5) a hydroxyl group, (6) a carboxyl group, (7) an optionallysubstituted C₂₋₇ alkoxycarbonyl group, (8) an optionally substituted 5-to 14-membered heterocyclic group, (9) an optionally substituted 5- to14-membered aromatic heterocyclic group, (10) an optionally substitutedC₆₋₁₄ aryl group, (11) a group represented by the formula—NR^(c21)R^(c22) (wherein R^(c21) and R^(c22) are each independently ahydrogen atom or an optionally substituted C₁₋₆ alkyl group), or (12) ahydrogen atom)];

-   <11> a compound represented by the following general formula:

[wherein R¹, R² and Z¹² have the same definitions as R¹, R² and Z¹² in<2>, but Z¹² is not a pyrazolyl group; Y^(a1) is a group represented bythe formula:

(wherein W³¹ and W³² are each independently an optionally substitutedcarbon atom or a nitrogen atom; R³⁰⁰ and R³⁰¹ are each independently ahydrogen atom, a halogen atom, a cyano group, a nitro group, an aminogroup, an optionally substituted C₁₋₆ alkyl group, an optionallysubstituted C₃₋₈ alicyclic hydrocarbon group, an optionally substitutedC₁₋₆ alkoxy group, an optionally substituted C₂₋₇ alkoxycarbonyl group,a formyl group, a group represented by the formula

(wherein V³⁰⁰ and V³⁰¹ are each independently a hydrogen atom or anoptionally substituted C₁₋₆ alkyl group), or an optionally substitutedC₂₋₇ acyl group); and R^(a11) and R^(a12) have the same definitions asR^(a11) and R^(a12) in <7>, with the exception of the followingcompounds (1) and (2): (1) a compound wherein R^(a12) is a grouprepresented by the formula:

(wherein V^(a12) and V^(a13) have the same definitions as V^(a12) andV^(a13) in <7>), R¹ and R² are hydrogen atoms and Z¹² is a C₆₋₁₄ arylgroup, a 6- to 14-membered heterocyclic group or a 6- to 14-memberedaromatic heterocyclic group; (2) a compound wherein R^(a12) is a groupselected from the group consisting of the formulas:

(wherein V^(a11), V^(a12), V^(a13) and V^(a14) have the same definitionsas V^(a11), V^(a12), V^(a13) and V^(a14) in <7>), R² is a hydrogen atomand Z¹² is (a) a C₆₋₁₄ aryl group, (b) a 5- to 14-membered heterocyclicgroup, (c) a 5- to 14-membered aromatic heterocyclic group, (d) a C₁₋₆alkyl group substituted with a 5- to 10-membered heterocyclic group or aC₅₋₁₀ alicyclic hydrocarbon group, (e) a C₂₋₆ alkenyl group substitutedwith a 5- to 10-membered heterocyclic group or a C₅₋₁₀ alicyclichydrocarbon group, (f) a C₂₋₆ alkynyl group substituted with a 5- to10-membered heterocyclic group or a C₅₋₁₀ alicyclic hydrocarbon group,or (g) a C₃₋₈ alicyclic hydrocarbon group substituted with a 5- to10-membered heterocyclic group or a C₅₋₁₀ alicyclic hydrocarbon group],a salt thereof or a hydrate of the foregoing;

-   <12> a compound according to <11>, a salt of the compound or a    hydrate of the foregoing, wherein R^(a11) is a methyl group, a    2-methoxyethyl group or a group represented by the formula:

(wherein R^(a53) is a methyl group, a cyclopropylmethyl group or acyanomethyl group; R^(a51) is a hydrogen atom, a fluorine atom or ahydroxyl group; and R^(a52) is a 1-pyrrolidinyl group, a 1-piperidinylgroup, a 4-morpholinyl group, a dimethylamino group or a diethylaminogroup);

-   <13> a compound according to <11> or <12>, a salt of the compound or    a hydrate of the foregoing, wherein Z¹² is a methyl group, an ethyl    group, a cyclopropyl group, a 2-thiazolyl group or a 4-fluorophenyl    group;-   <14> a compound according to any one of <11> to <13>, a salt of the    compound or a hydrate of the foregoing, wherein Y^(a1) is a group    represented by the formula:

(wherein R^(a61) is a hydrogen atom, a methyl group, a trifluoromethylgroup, a chlorine atom or a fluorine atom);

-   <15> a compound according to any one of <11> to <14>, a salt of the    compound or a hydrate of the foregoing, wherein R^(a12) is a cyano    group or a group represented by the formula —CONHR^(a62) (wherein    R^(a62) is a hydrogen atom, an optionally substituted C₁₋₆ alkyl    group, an optionally substituted C₃₋₈ alicyclic hydrocarbon group,    an optionally substituted C₁₋₆ alkoxy group or an optionally    substituted C₃₋₈ cycloalkoxy group);-   <16> a compound represented by the following general formula:

[wherein Z²¹ is a hydrogen atom, an optionally substituted C₁₋₆ alkylgroup, an optionally substituted C₂₋₆ alkenyl group, an optionallysubstituted C₂₋₆ alkynyl group or an optionally substituted C₃₋₈alicyclic hydrocarbon group; R^(a120) is a cyano group or a grouprepresented by the formula:

(wherein V^(a15) is an optionally substituted C₁₋₆ alkyl group, anoptionally substituted C₂₋₆ alkenyl group, an optionally substitutedC₂₋₆ alkynyl group or an optionally substituted C₃₋₈ alicyclichydrocarbon group, and V^(a11), V^(a12), V^(a13) and V^(a14) have thesame definitions as V^(a11), V^(a12), V^(a13) and V^(a14) in <7>); R³⁰⁰and R³⁰¹ have the same definitions as R³⁰⁰ and R³⁰¹ in <11>; and R^(a11)has the same definition as R^(a11) in <7>, with the exception of acompound wherein R^(a120) is a group selected from the group consistingof the formulas:

(wherein V^(a11), V^(a12), V^(a13) and V^(a14) have the same definitionsas V^(a11), V^(a12), V^(a13) and V^(a14) in <7>, and V^(a15) is asdefined above), and Z²¹ is (a) a C₃₋₈ alicyclic hydrocarbon group, (b) aC₁₋₆ alkyl group substituted with a 5- to 10-membered heterocyclic groupor a C₅₋₂₀ alicyclic hydrocarbon group, (c) a C₂₋₆ alkenyl groupsubstituted with a 5- to 10-membered heterocyclic group or a C₅₋₁₀alicyclic hydrocarbon group, or (d) a C₂₋₆ alkynyl group substitutedwith a 5- to 10-membered heterocyclic group or a C₅₋₁₀ alicyclichydrocarbon group], a salt thereof or a hydrate of the foregoing;

-   <17> a compound represented by the following general formula:

[wherein Z²² is an optionally substituted C₆₋₁₄ aryl group, anoptionally substituted 5- to 14-membered heterocyclic group or anoptionally substituted 5- to 14-membered aromatic heterocyclic group;R³⁰⁰ and R³⁰¹ have the same definitions as R³⁰⁰ and R³⁰¹ in <11>;V^(d13) is a group selected from the group consisting of the formulas:

(wherein V^(a12) and V^(a13) have the same definitions as V^(a12) andV^(a13) in <7>); V^(d11) is an optionally substituted C₁₋₆ alkylenegroup or a group represented by the formula:

and V^(d12) is (1) a group represented by the formula —NR^(d11)R^(d12)(wherein R^(d11) and R^(d12) are each a hydrogen atom, an optionallysubstituted C₁₋₆ alkyl group, an optionally substituted C₃₋₈ alicyclichydrocarbon group, an optionally substituted C₆₋₁₄ aryl group, anoptionally substituted 5- to 14-membered heterocyclic group or anoptionally substituted 5- to 14-membered aromatic heterocyclic group),or (2) an optionally substituted 5- to 14-membered heterocyclic group],a salt thereof or a hydrate of the foregoing;

-   <18> a compound represented by the following general formula:

[wherein R¹, R² and Z¹² have the same definitions as R¹, R² and Z¹² in<2>; W¹¹ is an optionally substituted carbon atom or a nitrogen atom;R³⁰⁰ has the same definition as R³⁰⁰ in <11>; R^(a11) has the samedefinition as R¹¹ in <7>; and R^(a120) has the same definition asR^(a120) in <16>, with the exception of the following compounds (1) and(2): (1) a compound wherein R^(a120) is a group represented by theformula:

(wherein V^(a12) and V^(a13) have the same definitions as V^(a12) andV^(a13 in <)7>) R¹ and R² are hydrogen atoms and Z¹² is a C₆₋₁₄ arylgroup, a 6- to 14-membered heterocyclic group or a 6- to 14-memberedaromatic heterocyclic group; (2) a compound wherein R^(a120) is a groupselected from the group consisting of the formulas:

(wherein V^(a11), V^(a12), V^(a13) and V^(a14) have the same definitionsas V^(a11), V^(a12), V^(a13) and V^(a14) in <7>, and V^(a15) has thesame definition as V^(a15) in <16>), R² is a hydrogen atom and Z¹² is(a) a C₆₋₁₄ aryl group, (b) a 5- to 14-membered heterocyclic group, (c)a 5- to 14-membered aromatic heterocyclic group, (d) a C₁₋₆ alkyl groupsubstituted with a 5- to 10-membered heterocyclic group or a C₅₋₂₀alicyclic hydrocarbon group, (e) a C₂₋₆ alkenyl group substituted with a5- to 10-membered heterocyclic group or a C₅₋₁₀ alicyclic hydrocarbongroup, (f) a C₂₋₆ alkynyl group substituted with a 5- to 10-memberedheterocyclic group or a C₅₋₁₀ alicyclic hydrocarbon group, or (g) a C₃₋₈alicyclic hydrocarbon group substituted with a 5- to 10-memberedheterocyclic group or a C₅₋₁₀ alicyclic hydrocarbon group], a saltthereof or a hydrate of the foregoing;

-   <19> a compound represented by the following general formula:

[wherein W⁴¹ and W are each independently an optionally substitutedcarbon atom or a nitrogen atom, but W₄₁ and W are not both nitrogenatoms; X^(y1) is an optionally substituted group selected from the groupconsisting of the following formulas:

(wherein Z¹² has the same definition as Z¹² in <2>, and W¹¹ is anoptionally substituted carbon atom or a nitrogen atom); and A^(b11) hasthe same definition as A^(b11) in <9>], a salt thereof or a hydrate ofthe foregoing;

-   <20> a compound represented by the following general formula:

[wherein R^(c13) has the same definition as R^(c13) in <10>; X^(y2) isan optionally substituted group selected from the group consisting ofthe following formulas:

(wherein Z¹², R¹ and R² have the same definitions as Z¹², R¹ and R² in<2>, and W¹¹ is an optionally substituted carbon atom or a nitrogenatom); and R^(c11) and R^(c12) have the same definitions as R^(c11) andR^(c12) in <10>, with the exception of the following compounds (1) and(2): (1) a compound wherein R¹ and R² are hydrogen atoms and Z¹² is (a)a C₆₋₁₄ aryl group, (b) a 5- to 14-membered heterocyclic group, (c) aC₂₋₆ alkyl group substituted with a 5- to 14-membered aromaticheterocyclic group, a 5- to 10-membered heterocyclic group or a C₅₋₂₀alicyclic hydrocarbon group, (d) a C₂₋₆ alkenyl group substituted with a5- to 10-membered heterocyclic group or a C₅₋₂₀ alicyclic hydrocarbongroup, (e) a C₂₋₆ alkynyl group substituted with a 5- to 10-memberedheterocyclic group or a C₅₋₂₀ alicyclic hydrocarbon group, or (f) a C₃₋₈alicyclic hydrocarbon group substituted with a 5- to 10-memberedheterocyclic group or a C₅₋₁₀ alicyclic hydrocarbon group; (2) acompound wherein X^(y2) is a group represented by the formula:

(wherein Z¹² is (a) a C₆₋₁₄ aryl group, (b) a 5- to 14-memberedheterocyclic group, (c) a 5- to 14-membered aromatic heterocyclic group,(d) a C₁₋₆ alkyl group substituted with a 5- to 10-membered heterocyclicgroup or a C₅₋₁₀ alicyclic hydrocarbon group, (e) a C₂₋₆ alkenyl groupsubstituted with a 5- to 10-membered heterocyclic group or a C₅₋₁₀alicyclic hydrocarbon group, (f) a C₂₋₆ alkynyl group substituted with a5- to 10-membered heterocyclic group or a C₅₋₁₀ alicyclic hydrocarbongroup, or (g) a C₃₋₈ alicyclic hydrocarbon group)], a salt thereof or ahydrate of the foregoing;

-   <21> a compound according to <10> or <20>, a salt of the compound or    a hydrate of the foregoing, wherein R^(c11) is a group represented    by the formula:

[wherein V^(f11) is a single bond, an optionally substituted C₁₋₆alkylene group or a group represented by the formula:

and V^(f12) is (1) a hydrogen atom, (2) a hydroxyl group, (3) anoptionally substituted 5- to 14-membered heterocyclic group, (4) anoptionally substituted 5- to 14-membered aromatic heterocyclic group,(5) an optionally substituted C₆₋₁₄ aryl group or (6) a grouprepresented by the formula —NR^(f21)R^(f22) (wherein R^(f21) and R^(f22)are each independently a hydrogen atom or an optionally substituted C₁₋₆alkyl group)];

-   <22> a compound represented by the following general formula:

[wherein X has the same definition as X in <2>; R³⁰⁰ and R³⁰¹ have thesame definitions as R³⁰⁰ and R³⁰¹ in <11>; and A³¹ is a group selectedfrom the group consisting of the formulas:

(wherein R^(c13) has the same definition as R^(c13) in <10>; W, R^(a11)and R^(a13) have the same definitions as W, R^(a11) and R^(a13) in <7>;A^(b11) has the same definition as A^(b11) in <9>; R^(c12) has the samedefinition as R^(c12) in <10>; and R^(e11) is a group represented by theformula:

(wherein V^(f11) and V^(f12) have the same definitions as V^(f11) andV^(f12) in <21>, but V^(f12) is not a hydrogen atom))], a salt thereofor a hydrate of the foregoing;

-   <23> a compound represented by the following general formula:

[wherein Z¹², R¹ and R² have the same definitions as Z¹², R¹ and R² in<2>; R³⁰⁰ and R³⁰¹ have the same definitions as R³⁰⁰ and R³⁰¹ in <11>;and A³² is a group selected from the group consisting of the formulas:

(wherein R^(c13) has the same definition as R^(c13) in <10>; W, R^(a11),R^(a12) and R^(a13) have the same definitions as W, R^(a11), R^(a12) andR^(a13) in <7>; A^(b11) has the same definition as A^(b11) in <9>; andR^(c11) and R^(c12) have the same definitions as R^(c11) and R^(c12) in<10>)], a salt thereof or a hydrate of the foregoing;

-   <24> a compound according to <1> or <2>, a pharmacologically    acceptable salt of the compound or a hydrate of the foregoing,    wherein said compound is a compound selected from-   N-(4-(6-cyano-7-(3-(4-pyridyl)propoxy)-4-quinolyl)oxyphenyl)-N′-(4-methoxyphenyl)urea,-   N-(4-(6-cyano-7-(2-(1,2,3-triazol-2-yl)ethoxy)-4-quinolyl)oxyphenyl)-N′-(4-fluorophenyl)urea,-   N-(4-(6-cyano-7-(2-(1,2,3-triazol-1-yl)ethoxy)-4-quinolyl)oxyphenyl)-N′-(4-fluorophenyl)urea,-   N-(4-(6-cyano-7-(2-(1,2,3-triazol-2-yl)ethoxy)-4-quinolyl)oxyphenyl)-N′-(2,4-difluorophenyl)urea,-   N-(4-(6-cyano-7-(2-(1,2,3-triazol-1-yl)ethoxy)-4-quinolyl)oxyphenyl)-N′-(2,4-difluorophenyl)urea,-   N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)-N′-(4-fluorophenyl)urea,-   N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)-N′-(1,3-thiazol-2-yl)urea,-   N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)-N′-(3-cyanophenyl)urea,-   N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)-N′-(2-(methylsulfonyl)phenyl)urea,-   N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)-N′-cyclopropylurea,-   N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-(1,3-thiazol-2-yl)urea,-   N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-cyclopropylurea,-   N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)-N′-cyclopropylmethylurea,-   N-(4-(6-cyano-7-(3-(morpholin-4-yl)propoxy)quinolin-4-yloxy)-2-fluorophenyl)-N′-(2,4-difluorophenyl)urea,-   N-(4-(6-cyano-7-(3-(diethylamino)propoxy)-4-quinolyloxyphenyl)-N′-(4-fluorophenyl)urea,-   N-(4-(6-cyano-7-(3-(4-morpholino)propoxy)-4-quinolyl)oxyphenyl)-N′-(4-fluorophenyl)urea,-   N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-(3-(methylsulfonyl)phenyl)urea,-   N-(4-(6-cyano-7-(3-(diethylamino)propoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-(2,4-difluorophenyl)urea,-   N-(4-(6-cyano-7-(3-(1-(4-ethylpiperazino))propoxy)-4-quinolyl)oxyphenyl)-N′-(4-methoxyphenyl)urea,-   N-(4-(6-cyano-7-(3-cyanopropoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-(2,4-difluorophenyl)urea,-   N-(4-(6-cyano-7-(2-(methylsulfonyl)ethoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-(2,4-difluorophenyl)urea,-   N-(4-(6-cyano-7-(2-(methylsulfonyl)ethoxy)-4-quinolyl)oxyphenyl)-N′-(4-fluorophenyl)urea,-   N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)-N′-phenylurea,-   N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-(2,4-difluorophenyl)urea,-   N-(4-(6-cyano-7-(3-methoxycarbonylpropoxy)-4-quinolyl)oxyphenyl)-N′-(4-methoxyphenyl)urea,-   N-(4-(6-cyano-7-(3-carboxypropoxy)-4-quinolyl)oxyphenyl)-N′-(4-methoxyphenyl)urea,-   N-(4-(6-cyano-7-(2-(2-hydroxyethoxy)ethoxy)-4-quinolyl)oxyphenyl)-N′-(4-methoxyphenyl)urea,-   N-(4-(6-cyano-7-(3-(diethylamino)propoxy)-4-quinolyloxy)phenyl)-N′-(3-(methylsulfonyl)phenyl)urea,-   N-(4-(6-cyano-7-(3-(4-morpholino)propoxy)-4-quinolyl)oxyphenyl)-N′-(3-(methylsulfonyl)phenyl)urea,-   N-(4-(6-cyano-7-(3-(diethylamino)propoxy)-4-quinolyloxy)phenyl)-N′-phenylurea,-   N-(4-(6-cyano-7-(3-(4-morpholino)propoxy)-4-quinolyl)oxyphenyl)-N′-phenylurea,-   N-(4-(6-cyano-7-(3-(4-morpholino)propoxy)-4-quinolyl)oxyphenyl)-N′-(2-oxo-1,2,3,4-tetrahydro-6-quinolyl)urea,-   N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)-N′-(3-acetamidophenyl)urea,-   N-(4-(6-cyano-7-benzyloxy-4-quinolyl)oxy-2-fluorophenyl)-N′-(2,4-difluorophenyl)urea,-   N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-(4-fluorophenyl)urea,-   N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-phenylurea,-   4-(4-((4-fluoroanilino)carbonyl)aminophenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxamide,-   7-(2-methoxyethoxy)-4-(4-((1,3-thiazol-2-ylamino)carbonyl)aminophenoxy)-6-quinolinecarboxamide,-   4-(4-((anilinocarbonyl)amino)-3-fluorophenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxamide,-   4-(4-((4-fluoroanilino)carbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide,-   4-(4-((cyclopropylamino)carbonyl)aminophenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxamide,-   7-methoxy-4-(4-((1,3-thiazol-2-ylamino)carbonyl)aminophenoxy)-6-quinolinecarboxamide,-   4-(4-((2,4-difluoroanilino)carbonyl)amino-3-fluorophenoxy)-7-methoxy-6-quinolinecarboxamide,-   4-(4-((cyclopropylamino)carbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide,-   4-(5-((anilinocarbonyl)amino)-2-pyridyloxy)-7-methoxy-6-quinolinecarboxamide,-   4-(4-(anilinocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide,-   4-(4-(anilinocarbonyl)aminophenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxamide,-   4-(4-((2,4-difluoroanilino)carbonyl)amino-3-fluorophenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxamide,-   4-(4-((4-fluoroanilino)carbonyl)amino-3-fluorophenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxamide,-   7-(2-methoxyethoxy)-4-(4-((1,3-thiazol-2-ylamino)carbonyl)amino-3-fluorophenoxy)-6-quinolinecarboxamide    and-   4-(4-((4-fluoroanilino)carbonyl)amino-3-fluorophenoxy)-7-methoxy-6-quinolinecarboxamide;-   <25> a compound according to <1> or <2>, a pharmacologically    acceptable salt of the compound or a hydrate of the foregoing,    wherein said compound is a compound selected from-   N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-(4-fluorophenyl)urea,-   N-(2-chloro-4-((6-cyano-7-((1-methyl-4-piperidyl)methoxy)-4-quinolyl)oxy)phenyl)-N′-cyclopropylurea,-   N-(4-((6-cyano-7-(((2R)-3-(diethylamino)-2-hydroxypropyl)oxy)-4-quinolyl)oxy)phenyl)-N′-(4-fluorophenyl)urea,-   N-(4-((6-cyano-7-(((2R)-2-hydroxy-3-(1-pyrrolidino)propyl)oxy)-4-quinolyl)oxy)phenyl)-N′-(4-fluorophenyl)urea,-   N-{4-[6-cyano-7-(2-hydroxy-3-pyrrolidin-1-yl-propoxy)-quinolin-4-yloxy]-2-methylphenyl}-N′-cyclopropyl-urea,-   4-(4-(4-fluoroanilino)carbonyl)-4-methylaminophenoxy)-7-methoxy-6-quinolinecarboxamide,-   4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide,-   4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxamide,-   N6-cyclopropyl-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide,-   N6-(2-methoxyethyl)-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide,-   N6-(2-pyridyl)-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide,-   N6-(2-fluoroethyl)-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide,-   N6-methoxy-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide,-   N6-methyl-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide,-   N6-ethyl-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide,-   6-carbamoyl-4-(1-ethylcarbamoyl-1H-indol-5-yloxy)-7-methoxyquinoline,-   6-carbamoyl-7-methoxy-4-(1-propylcarbamoyl-1H-indol-5-yloxy)quinoline,-   6-carbamoyl-7-methoxy-4-[1-(1-methyl)ethylcarbamoyl-1H-indol-5-yloxy]quinoline,-   N4-(4-{4-[(anilinocarbonyl)amino]-3-chlorophenoxy}-2-pyridyl)-1-methyl-4-piperidinecarboxamide,-   N1-phenyl-3-chloro-5-[(2-{[(1-methyl-4-piperidyl)carbonyl]amino}-4-pyridyl)oxy]-1H-1-indolecarboxamide,-   N4-[4-(3-chloro-4-{[(4-fluoroanilino)carbonyl]amino}phenoxy)-2-pyridyl]-1-methyl-4-piperidinecarboxamide,-   1-(2-chloro-4-{6-[4-(2-diethylaminoethoxy)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy}phenyl)-3-cyclopropylurea,-   1-{2-chloro-4-[6-[4-((2R)-2-hydroxy-3-diethylaminopropoxy)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]-phenyl}-3-cyclopropylurea,-   1-(2-chloro-4-{6-[4-((2R)-2-hydroxy-3-pyrrolidinopropoxy)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy}-phenyl)-3-cyclopropylurea    and-   1-(2-chloro-4-{6-[4-(2-diethylaminopropoxy)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy}phenyl)-3-cyclopropylurea;-   <26> a compound according to <1> or <2>, a pharmacologically    acceptable salt of the compound or a hydrate of the foregoing,    wherein said compound is a compound selected from-   4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide,-   4-(3-chloro-4-(ethylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide,-   N6-methoxy-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide,-   4-(3-chloro-4-(methylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide    and-   N6-methoxy-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide;-   <27> a medicament (a drug) comprising as an active ingredient, a    compound according to any one of <1> to <6>, a pharmacologically    acceptable salt thereof or a hydrate of the foregoing;-   <28> an angiogenesis inhibiting activity-based medicament (an    angiogenesis inhibiting activity-based drug) comprising as an active    ingredient, a compound according to any one of <1> to <6>, a    pharmacologically acceptable salt thereof or a hydrate of the    foregoing;-   <29> a pharmaceutical composition comprising a compound represented    by the general formula:

[wherein A is an optionally substituted 5- to 14-membered aromaticheterocyclic group; X is an oxygen atom, a sulfur atom, —SO— or —SO₂; Yis an optionally substituted C₆₋₁₄ aryl group, an optionally substituted5- to 14-membered aromatic heterocyclic group or an optionallysubstituted C₁₋₆ alkylene group; E is a single bond or —NR²—; R¹ and R²are each independently a hydrogen atom, an optionally substituted C₁₋₆alkyl group, an optionally substituted C₂₋₆ alkenyl group, an optionallysubstituted C₂₋₆ alkynyl group, an optionally substituted C₃₋₈ alicyclichydrocarbon group, an optionally substituted C₂₋₇ acyl group or anoptionally substituted C₂₋₇ alkoxycarbonyl group; and Z is a grouprepresented by the formula —Z¹¹—Z¹² (wherein Z¹¹ is a single bond, anoxygen atom, a sulfur atom, —CO—, —SO₂— or an optionally substitutedC₁₋₆ alkylene group and Z¹² is a hydrogen atom, an optionallysubstituted C₁₋₆ alkyl group, an optionally substituted C₂₋₆ alkenylgroup, an optionally substituted C₂₋₆ alkynyl group, an optionallysubstituted C₃₋₈ alicyclic hydrocarbon group, an optionally substitutedC₆₋₁₄ aryl group, an optionally substituted 5- to 14-memberedheterocyclic group, an optionally substituted 5- to 14-membered aromaticheterocyclic group or a group represented by the formula:

(wherein Z³¹, Z³³ and Z³⁴ are each independently a methylene group,—CO—, —NH— or —O—, and Z³² is a single bond, a methylene group, —CO—,—NH— or —O—)), with the proviso that A may be optionally substitutedwith 1 to 6 groups, each selected from the group consisting of (1) acyano group, (2) a halogen atom, (3) a nitro group and (4) the formula—V^(X1)—V^(X2)—V^(X22)—V^(X3) (wherein V^(X1), V^(X2) and V^(X22) areeach independently a single bond, an oxygen atom, a sulfur atom, —CO—,—SO—, —SO₂—, —NR^(X1)—, —CONR^(X1)—, NR^(X1)CO—, —SO₂NR^(X1)—,—NR^(X1)SO₂—, —O —CO—, —C(O)O—, —NR^(X1)C(O)O—, —NR^(X1)C(O)NR^(X2)—,—O—C(O)NR^(X1)—, —O—C(O)O—, an optionally substituted C₁₋₆ alkylenegroup, an optionally substituted C₂₋₆ alkenyl group, an optionallysubstituted C₂₋₆ alkynyl group, an optionally substituted C₃₋₈ alicyclichydrocarbon group, an optionally substituted C₆₋₁₄ aryl group, anoptionally substituted 5- to 14-membered heterocyclic group or anoptionally substituted 5- to 14-membered aromatic heterocyclic group;and V^(X3), R^(X1) and R^(X2) are each independently a hydrogen atom, anoptionally substituted C₁₋₆ alkyl group, an optionally substituted C₂₋₆alkenyl group, an optionally substituted C₂₋₆ alkynyl group, anoptionally substituted C₃₋₈ alicyclic hydrocarbon group, an optionallysubstituted C₆₋₁₄ aryl group, an optionally substituted 5- to14-membered heterocyclic group, an optionally substituted 5- to14-membered aromatic heterocyclic group or an optionally substitutedC₁₋₆ alkoxy group)], a pharmacologically acceptable salt thereof or ahydrate of the foregoing, together with a pharmacologically acceptablecarrier;

-   <30> a prophylactic or therapeutic agent for a disease for which    angiogenesis inhibition is effective, comprising as an active    ingredient, a compound according to <1> or <2>, a pharmacologically    acceptable salt thereof or a hydrate of the foregoing;-   <31> an angiogenesis inhibitor comprising as an active ingredient, a    compound according to <1> or <2>, a pharmacologically acceptable    salt thereof or a hydrate of the foregoing;-   <32> an antitumor agent comprising as an active ingredient, a    compound according to <1> or <2>, a pharmacologically acceptable    salt thereof or a hydrate of the foregoing;-   <33> a therapeutic agent for angioma (an angioma treatment agent)    comprising as an active ingredient, a compound according to <1> or    <2>, a pharmacologically acceptable salt thereof or a hydrate of the    foregoing;-   <34> a cancer metastasis inhibitor comprising as an active    ingredient, a compound according to <1> or <2>, a pharmacologically    acceptable salt thereof or a hydrate of the foregoing;-   <35> a therapeutic agent for retinal neovascularization or diabetic    retinopathy (a retinal neovascularization treatment agent or    diabetic retinopathy treatment agent) comprising as an active    ingredient, a compound according to <1> or <2>, a pharmacologically    acceptable salt thereof or a hydrate of the foregoing;-   <36> a therapeutic agent for an inflammatory disease (an    inflammatory disease treatment agent) comprising as an active    ingredient, a compound according to <1> or <2>, a pharmacologically    acceptable salt thereof or a hydrate of the foregoing;-   <37> a therapeutic agent for an inflammatory disease selected from    deformant arthritis, rheumatoid arthritis, psoriasis and delayed    hypersensitivity reaction (an inflammatory disease treatment agent    for deformant arthritis, rheumatoid arthritis, psoriasis or delayed    hypersensitivity reaction) comprising as an active ingredient, a    compound according to <1> or <2>, a pharmacologically acceptable    salt thereof or a hydrate of the foregoing;-   <38> a therapeutic agent for atherosclerosis (an atherosclerosis    treatment agent) comprising as an active ingredient, a compound    according to <1> or <2>, a pharmacologically acceptable salt thereof    or a hydrate of the foregoing;-   <39> a therapeutic agent for a pancreatic cancer, a gastric cancer,    a colon cancer, abreast cancer, a prostate cancer, a lung cancer, a    renal cancer, a brain tumor, a blood cancer or an ovarian cancer (a    pancreatic cancer treatment agent, a gastric cancer treatment agent,    a colon cancer treatment agent, a breast cancer treatment agent, a    prostate cancer treatment agent, a pulmonary cancer treatment agent,    a renal cancer treatment agent, a brain tumor treatment agent, a    blood cancer treatment agent or an ovarian cancer treatment agent)    comprising as an active ingredient, a compound according to <1> or    <2>, a pharmacologically acceptable salt thereof or a hydrate of the    foregoing;-   <40> an angiogenesis inhibition-based antitumor agent comprising as    an active ingredient, a compound according to <1> or <2>, a    pharmacologically acceptable salt thereof or a hydrate of the    foregoing;-   <41> a prophylactic or therapeutic method for a disease for which    angiogenesis inhibition is effective, comprising administering to a    patient, a pharmacologically effective dose of a compound according    to <1> or <2>, a pharmacologically acceptable salt thereof or a    hydrate of the foregoing;-   <42> The use of a compound according to <1> or <2>, a    pharmacologically acceptable salt thereof or a hydrate of the    foregoing for the manufacture of a prophylactic or a therapeutic    agent for a disease for which angiogenesis inhibition is effective.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention will now be explained in greater detail.

Several of the structural formulas given for compounds throughout thepresent specification will represent a specific isomer for convenience,but the invention is not limited to such specific isomers andencompasses all isomers and isomer mixtures, including geometricisomers, asymmetric carbon-derived optical isomers, stereoisomers andtautomers, implied by the structures of the compounds. Moreover, thecompounds of the invention also include those that have been metabolizedin the body by oxidation, reduction, hydrolysis, conjugation or thelike, and still exhibit the desired activity, while the inventionfurther encompasses all compounds which undergo metabolism such asoxidation, reduction, hydrolysis, etc. in the body to produce thecompounds of the invention. Solvates, including those with water, arealso encompassed by the invention.

The terms used throughout the present specification will now be defined.

The term “halogen atom” as used throughout the present specificationrefers to halogen atoms such as fluorine, chlorine, bromine and iodine,with fluorine, chlorine and bromine being preferred.

The term “C₁₋₆ alkyl group” as used throughout the present specificationrefers to a linear or branched alkyl group of 1 to 6 carbons, and asspecific examples there may be mentioned methyl, ethyl, n-propyl,i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, i-pentyl,sec-pentyl, t-pentyl, neopentyl, 1-methylbutyl, 2-methylbutyl,1,1-dimethylpropyl, 1,2-dimethylpropyl, n-hexyl, i-hexyl,1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl,1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl,2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl,1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and1-ethyl-2-methylpropyl, preferably methyl, ethyl, n-propyl, i-propyl,n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, i-pentyl, sec-pentyl,t-pentyl, neopentyl, 1-methylbutyl, 2-methylbutyl, 1,1-dimethylpropyl,1,2-dimethylpropyl, n-hexyl and i-hexyl, more preferably methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl,i-pentyl, sec-pentyl, t-pentyl, neopentyl, 1-methylbutyl, 2-methylbutyl,1, 1-dimethylpropyl and 1, 2-dimethylpropyl, even more preferablymethyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl andt-butyl, and most preferably methyl, ethyl, n-propyl and i-propyl.

The term “C₁₋₆ alkylene group” as used throughout the presentspecification refers to a divalent group derived by removing onehydrogen atom from the aforementioned “C₁₋₆ alkyl group”, and asspecific examples there may be mentioned methylene, ethylene,methylethylene, propylene, ethylethylene, 1,1-dimethylethylene,1,2-dimethylethylene, trimethylene, 1-methyltrimethylene,1-ethyltrimethylene, 2-methyltrimethylene, 1,1-dimethyltrimethylene,tetramethylene, pentamethylene and hexamethylene.

The term “C₂₋₆ alkenyl group” as used throughout the presentspecification refers to a linear or branched alkenyl group of 2 to 6carbons, and it is a substituent with a double bond in a “C₁₋₆ alkylgroup” of 2 or more carbons. As specific examples there may be mentionedethenyl, 1-propen-1-yl, 2-propen-1-yl, 3-propen-1-yl, 1-buten-1-yl,1-buten-2-yl, 1-buten-3-yl, 1-buten-4-yl, 2-buten-1-yl, 2-buten-2-yl,1-methyl-1-propen-1-yl, 2-methyl-1-propen-1-yl, 1-methyl-2-propen-1-yl,2-methyl-2-propen-1-yl, 1-methyl-1-buten-1-yl, 2-methyl-1-buten-1-yl,3-methyl-1-buten-1-yl, 1-methyl-2-buten-1-yl, 2-methyl-2-buten-1-yl,3-methyl-2-buten-1-yl, 1-methyl-3-buten-1-yl, 2-methyl-3-buten-1-yl,3-methyl-3-buten-1-yl, 1-ethyl-1-buten-1-yl, 2-ethyl-1-buten-1-yl,3-ethyl-1-buten-1-yl, 1-ethyl-2-buten-1-yl, 2-ethyl-2-buten-1-yl,3-ethyl-2-buten-1-yl, 1-ethyl-3-buten-1-yl, 2-ethyl-3-buten-1-yl,3-ethyl-3-buten-1-yl, 1,1-dimethyl-1-buten-1-yl,1,2-dimethyl-1-buten-1-yl, 1,3-dimethyl-1-buten-1-yl,2,2-dimethyl-1-buten-1-yl, 3,3-dimethyl-1-buten-1-yl,1,1-dimethyl-2-buten-1-yl, 1,2-dimethyl-2-buten-1-yl,1,3-dimethyl-2-buten-1-yl, 2,2-dimethyl-2-buten-1-yl,3,3-dimethyl-2-buten-1-yl, 1,1-dimethyl-3-buten-1-yl,1,2-dimethyl-3-buten-1-yl, 1,3-dimethyl-3-buten-1-yl,2,2-dimethyl-3-buten-1-yl, 3,3-dimethyl-3-buten-1-yl, 1-penten-1-yl,2-penten-1-yl, 3-penten-1-yl, 4-penten-1-yl, 1-penten-2-yl,2-penten-2-yl, 3-penten-2-yl, 4-penten-2-yl, 1-penten-3-yl,2-penten-3-yl, 1-methyl-1-penten-1-yl, 2-methyl-1-penten-1-yl,3-methyl-1-penten-1-yl, 4-methyl-1-penten-1-yl, 1-methyl-2-penten-1-yl,2-methyl-2-penten-1-yl, 3-methyl-2-penten-1-yl, 4-methyl-2-penten-1-yl,1-methyl-3-penten-1-yl, 2-methyl-3-penten-1-yl, 3-methyl-3-penten-1-yl,4-methyl-3-penten-1-yl, 1-methyl-4-penten-1-yl, 2-methyl-4-penten-1-yl,3-methyl-4-penten-1-yl, 4-methyl-4-penten-1-yl, 1-methyl-1-penten-2-yl,2-methyl-1-penten-2-yl, 3-methyl-1-penten-2-yl, 4-methyl-1-penten-2-yl,1-methyl-2-penten-2-yl, 2-methyl-2-penten-2-yl, 3-methyl-2-penten-2-yl,4-methyl-2-penten-2-yl, 1-methyl-3-penten-2-yl, 2-methyl-3-penten-2-yl,3-methyl-3-penten-2-yl, 4-methyl-3-penten-2-yl, 1-methyl-4-penten-2-yl,2-methyl-4-penten-2-yl, 3-methyl-4-penten-2-yl, 4-methyl-4-penten-2-yl,1-methyl-1-penten-3-yl, 2-methyl-1-penten-3-yl, 3-methyl-1-penten-3-yl,4-methyl-1-penten-3-yl, 1-methyl-2-penten-3-yl, 2-methyl-2-penten-3-yl,3-methyl-2-penten-3-yl, 4-methyl-2-penten-3-yl, 1-hexen-1-yl,1-hexen-2-yl, 1-hexen-3-yl, 1-hexen-4-yl, 1-hexen-5-yl, 1-hexen-6-yl,2-hexen-1-yl, 2-hexen-2-yl, 2-hexen-3-yl, 2-hexen-4-yl, 2-hexen-5-yl,2-hexen-6-yl, 3-hexen-1-yl, 3-hexen-2-yl, 3-hexen-3-yl, preferablyethenyl, 1-propen-1-yl, 2-propen-1-yl, 3-propen-1-yl, 1-buten-1-yl,1-buten-2-yl, 1-buten-3-yl, 1-buten-4-yl, 2-buten-1-yl, 2-buten-2-yl,1-methyl-1-propen-1-yl, 2-methyl-1-propen-1-yl, 1-methyl-2-propen-1-yl,2-methyl-2-propen-1-yl, 1-methyl-1-buten-1-yl, 2-methyl-1-buten-1-yl,3-methyl-1-buten-1-yl, 1-methyl-2-buten-1-yl, 2-methyl-2-buten-1-yl,3-methyl-2-buten-1-yl, 1-methyl-3-buten-1-yl, 2-methyl-3-buten-1-yl,3-methyl-3-buten-1-yl, 1-ethyl-1-buten-1-yl, 2-ethyl-1-buten-1-yl,3-ethyl-1-buten-1-yl, 1-ethyl-2-buten-1-yl, 2-ethyl-2-buten-1-yl,3-ethyl-2-buten-1-yl, 1-ethyl-3-buten-1-yl, 2-ethyl-3-buten-1-yl,3-ethyl-3-buten-1-yl, 1,1-dimethyl-1-buten-1-yl,1,2-dimethyl-1-buten-1-yl, 1,3-dimethyl-1-buten-1-yl,2,2-dimethyl-1-buten-1-yl, 3,3-dimethyl-1-buten-1-yl,1,1-dimethyl-2-buten-1-yl, 1,2-dimethyl-2-buten-1-yl,1,3-dimethyl-2-buten-1-yl, 2,2-dimethyl-2-buten-1-yl,3,3-dimethyl-2-buten-1-yl, 1,1-dimethyl-3-buten-1-yl,1,2-dimethyl-3-buten-1-yl, 1,3-dimethyl-3-buten-1-yl,2,2-dimethyl-3-buten-1-yl and 3,3-dimethyl-3-buten-1-yl, more preferablyethenyl, 1-propen-1-yl, 2-propen-1-yl, 3-propen-1-yl, 1-buten-1-yl,1-buten-2-yl, 1-buten-3-yl, 1-buten-4-yl, 2-buten-1-yl, 2-buten-2-yl,1-methyl-1-propen-1-yl, 2-methyl-1-propen-1-yl, 1-methyl-2-propen-1-yl,2-methyl-2-propen-1-yl, 1-methyl-1-buten-1-yl, 2-methyl-1-buten-1-yl,3-methyl-1-buten-1-yl, 1-methyl-2-buten-1-yl, 2-methyl-2-buten-1-yl,3-methyl-2-buten-1-yl, 1-methyl-3-buten-1-yl, 2-methyl-3-buten-1-yl and3-methyl-3-buten-1-yl, and most preferably ethenyl, 1-propen-1-yl,2-propen-1-yl, 3-propen-1-yl, 1-buten-1-yl, 1-buten-2-yl, 1-buten-3-yl,1-buten-4-yl, 2-buten-1-yl and 2-buten-2-yl.

The term “C₂₋₆ alkynyl group” as used throughout the presentspecification refers to a linear or branched alkynyl group of 2 to 6carbons, and it is a substituent with a triple bond in a “C₁₋₆ alkylgroup” of 2 or more carbons. As specific examples there may be mentionedethynyl, 1-propyn-1-yl, 2-propyn-1-yl, 3-propyn-1-yl, 1-butyn-1-yl,1-butyn-2-yl, 1-butyn-3-yl, 1-butyn-4-yl, 2-butyn-1-yl, 2-butyn-2-yl,1-methyl-1-propyn-1-yl, 2-methyl-1-propyn-1-yl, 1-methyl-2-propyn-1-yl,2-methyl-2-propyn-1-yl, 1-methyl-1-butyn-1-yl, 2-methyl-1-butyn-1-yl,3-methyl-1-butyn-1-yl, 1-methyl-2-butyn-1-yl, 2-methyl-2-butyn-1-yl,3-methyl-2-butyn-1-yl, 1-methyl-3-butyn-1-yl, 2-methyl-3-butyn-1-yl,3-methyl-3-butyn-1-yl, 1-ethyl-1-butyn-1-yl, 2-ethyl-1-butyn-1-yl,3-ethyl-1-butyn-1-yl, 1-ethyl-2-butyn-1-yl, 2-ethyl-2-butyn-1-yl,3-ethyl-2-butyn-1-yl, 1-ethyl-3-butyn-1-yl, 2-ethyl-3-butyn-1-yl,3-ethyl-3-butyn-1-yl, 1,1-dimethyl-1-butyn-1-yl,1,2-dimethyl-1-butyn-1-yl, 1,3-dimethyl-1-butyn-1-yl,2,2-dimethyl-1-butyn-1-yl, 3,3-dimethyl-1-butyn-1-yl,1,1-dimethyl-2-butyn-1-yl, 1,2-dimethyl-2-butyn-1-yl,1,3-dimethyl-2-butyn-1-yl, 2,2-dimethyl-2-butyn-1-yl,3,3-dimethyl-2-butyn-1-yl, 1,1-dimethyl-3-butyn-1-yl,1,2-dimethyl-3-butyn-1-yl, 1,3-dimethyl-3-butyn-1-yl,2,2-dimethyl-3-butyn-1-yl, 3,3-dimethyl-3-butyn-1-yl, 1-pentyn-1-yl,2-pentyn-1-yl, 3-pentyn-1-yl, 4-pentyn-1-yl, 1-pentyn-2-yl,2-pentyn-2-yl, 3-pentyn-2-yl, 4-pentyn-2-yl, 1-pentyn-3-yl,2-pentyn-3-yl, 1-methyl-1-pentyn-1-yl, 2-methyl-1-pentyn-1-yl,3-methyl-1-pentyn-1-yl, 4-methyl-1-pentyn-1-yl, 1-methyl-2-pentyn-1-yl,2-methyl-2-pentyn-1-yl, 3-methyl-2-pentyn-1-yl, 4-methyl-2-pentyn-1-yl,1-methyl-3-pentyn-1-yl, 2-methyl-3-pentyn-1-yl, 3-methyl-3-pentyn-1-yl,4-methyl-3-pentyn-1-yl, 1-methyl-4-pentyn-1-yl, 2-methyl-4-pentyn-1-yl,3-methyl-4-pentyn-1-yl, 4-methyl-4-pentyn-1-yl, 1-methyl-1-pentyn-2-yl,2-methyl-1-pentyn-2-yl, 3-methyl-1-pentyn-2-yl, 4-methyl-1-pentyn-2-yl,1-methyl-2-pentyn-2-yl, 2-methyl-2-pentyn-2-yl, 3-methyl-2-pentyn-2-yl,4-methyl-2-pentyn-2-yl, 1-methyl-3-pentyn-2-yl, 2-methyl-3-pentyn-2-yl,3-methyl-3-pentyn-2-yl, 4-methyl-3-pentyn-2-yl, 1-methyl-4-pentyn-2-yl,2-methyl-4-pentyn-2-yl, 3-methyl-4-pentyn-2-yl, 4-methyl-4-pentyn-2-yl,1-methyl-1-pentyn-3-yl, 2-methyl-1-pentyn-3-yl, 3-methyl-1-pentyn-3-yl,4-methyl-1-pentyn-3-yl, 1-methyl-2-pentyn-3-yl, 2-methyl-2-pentyn-3-yl,3-methyl-2-pentyn-3-yl, 4-methyl-2-pentyn-3-yl, 1-hexyn-1-yl,1-hexyn-2-yl, 1-hexyn-3-yl, 1-hexyn-4-yl, 1-hexyn-5-yl, 1-hexyn-6-yl,2-hexyn-1-yl, 2-hexyn-2-yl, 2-hexyn-3-yl, 2-hexyn-4-yl, 2-hexyn-5-yl,2-hexyn-6-yl, 3-hexyn-1-yl, 3-hexyn-2-yl and 3-hexyn-3-yl, preferablyethynyl, 1-propyn-1-yl, 2-propyn-1-yl, 3-propyn-1-yl, 1-butyn-1-yl,1-butyn-2-yl, 1-butyn-3-yl, 1-butyn-4-yl, 2-butyn-1-yl, 2-butyn-2-yl,1-methyl-1-propyn-1-yl, 2-methyl-1-propyn-1-yl, 1-methyl-2-propyn-1-yl,2-methyl-2-propyn-1-yl, 1-methyl-1-butyn-1-yl, 2-methyl-1-butyn-1-yl,3-methyl-1-butyn-1-yl, 1-methyl-2-butyn-1-yl, 2-methyl-2-butyn-1-yl,3-methyl-2-butyn-1-yl, 1-methyl-3-butyn-1-yl, 2-methyl-3-butyn-1-yl,3-methyl-3-butyn-1-yl, 1-ethyl-1-butyn-1-yl, 2-ethyl-1-butyn-1-yl,3-ethyl-1-butyn-1-yl, 1-ethyl-2-butyn-1-yl, 2-ethyl-2-butyn-1-yl,3-ethyl-2-butyn-1-yl, 1-ethyl-3-butyn-1-yl, 2-ethyl-3-butyn-1-yl,3-ethyl-3-butyn-1-yl, 1,1-dimethyl-1-butyn-1-yl,1,2-dimethyl-1-butyn-1-yl, 1,3-dimethyl-1-butyn-1-yl,2,2-dimethyl-1-butyn-1-yl, 3,3-dimethyl-1-butyn-1-yl,1,1-dimethyl-2-butyn-1-yl, 1,2-dimethyl-2-butyn-1-yl,1,3-dimethyl-2-butyn-1-yl, 2,2-dimethyl-2-butyn-1-yl,3,3-dimethyl-2-butyn-1-yl, 1,1-dimethyl-3-butyn-1-yl,1,2-dimethyl-3-butyn-1-yl, 1,3-dimethyl-3-butyn-1-yl,2,2-dimethyl-3-butyn-1-yl and 3,3-dimethyl-3-butyn-1-yl, more preferablyethynyl, 1-propyn-1-yl, 2-propyn-1-yl, 3-propyn-1-yl, 1-butyn-1-yl,1-butyn-2-yl, 1-butyn-3-yl, 1-butyn-4-yl, 2-butyn-1-yl, 2-butyn-2-yl,1-methyl-1-propyn-1-yl, 2-methyl-1-propyn-1-yl, 1-methyl-2-propyn-1-yl,2-methyl-2-propyn-1-yl, 1-methyl-1-butyn-1-yl, 2-methyl-1-butyn-1-yl,3-methyl-1-butyn-1-yl, 1-methyl-2-butyn-1-yl, 2-methyl-2-butyn-1-yl,3-methyl-2-butyn-1-yl, 1-methyl-3-butyn-1-yl, 2-methyl-3-butyn-1-yl and3-methyl-3-butyn-1-yl, even more preferably ethynyl, 1-propyn-1-yl,2-propyn-1-yl, 3-propyn-1-yl, 1-butyn-1-yl, 1-butyn-2-yl, 1-butyn-3-yl,1-butyn-4-yl, 2-butyn-1-yl and 2-butyn-2-yl, and most preferablyethynyl, 1-propyn-1-yl, 2-propyn-1-yl and 3-propyn-1-yl.

The term “C₃₋₈ cycloalkyl group” as used throughout the presentspecification refers to a cyclic alkyl group of 3 to 8 carbons, and asspecific examples there may be mentioned cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl, with cyclopropyl being preferred.

The term “C₃₋₈ cycloalkenyl group” as used throughout the presentspecification refers to a cyclic alkenyl group of 3 to 8 carbons, and asspecific examples there may be mentioned cyclopentenyl and cyclohexenyl.

The term “C₃₋₈ cycloalkynyl group” as used throughout the presentspecification refers to a cyclic alkynyl group of 3 to 8 carbons, and asa specific example there may be mentioned cyclohexynyl.

The term “C₃₋₈ cycloalkoxy group” as used throughout the presentspecification refers to a cyclic alkoxy group of 3 to 8 carbons, and asspecific examples there may be mentioned cyclopropoxy, cyclobutoxy,cyclopentyloxy and cyclohexyloxy, with cyclopropoxy being preferred.

The term “C₃₋₈ alicyclic hydrocarbon group” as used throughout thepresent specification refers to a cyclic hydrocarbon of 3 to 8 carbons,and it is a substituent whose definition includes that of theaforementioned “C₃₋₈ cycloalkyl group”, “C₃₋₈ cycloalkenyl group” and“C₃₋₈ cycloalkynyl group”, with cyclopropyl being preferred.

The term “C₁₋₆ alkoxy group” as used throughout the presentspecification refers to a substituent wherein the aforementioned “C₁₋₆alkyl group” is bonded to an oxygen atom, and as specific examples theremay be mentioned methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy,i-butoxy, sec-butoxy, t-butoxy, n-pentyloxy, i-pentyloxy, sec-pentyloxy,t-pentyloxy, neopentyloxy, 1-methylbutoxy, 2-methylbutoxy,1,1-dimethylpropoxy, 1,2-dimethylpropoxy, n-hexyloxy, i-hexyloxy,1-methylpentyloxy, 2-methylpentyloxy, 3-methylpentyloxy,1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 2,2-dimethylbutoxy,1,3-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy,1-ethylbutoxy, 2-ethylbutoxy, 1,1,2-trimethylpropoxy,1,2,2-trimethylpropoxy, 1-ethyl-1-methylpropoxy and1-ethyl-2-methylpropoxy, preferably methoxy, ethoxy, n-propoxy,i-propoxy, n-butoxy, i-butoxy, sec-butoxy, t-butoxy, n-pentyloxy,i-pentyloxy, sec-pentyloxy, t-pentyloxy, neopentyloxy, 1-methylbutoxy,2-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, n-hexyloxy andi-hexyloxy, more preferably methoxy, ethoxy, n-propoxy, i-propoxy,n-butoxy, i-butoxy, sec-butoxy, t-butoxy, n-pentyloxy, i-pentyloxy,sec-pentyloxy, t-pentyloxy, neopentyloxy, 1-methylbutoxy,2-methylbutoxy, 1,1-dimethylpropoxy and 1,2-dimethylpropoxy, even morepreferably methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy,sec-butoxy and t-butoxy, and most preferably methoxy, ethoxy, n-propoxyand i-propoxy.

The term “C₂₋₇ acyl group” as used throughout the present specificationrefers to a substituent wherein a carbonyl group is bonded to the end ofthe aforementioned “C₁₋₆ alkyl group”, “C₂₋₆ alkenyl group” or “C₂₋₆alkynyl group” or phenyl group, and as specific examples there may bementioned acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl,pivaloyl, hexanoyl, octanoyl, acryloyl, methacryloyl, crotonyl andbenzoyl, preferably acetyl, propionyl, butyryl, isobutyryl, valeryl,isovaleryl, pivaloyl, hexanoyl, octanoyl, acryloyl, methacryloyl,crotonyl and benzoyl, more preferably acetyl, propionyl, butyryl,isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, octanoyl andbenzoyl, even more preferably acetyl, propionyl, butyryl, isobutyryl andbenzoyl, and most preferably acetyl, propionyl and benzoyl.

The term “C₂₋₇ alkoxycarbonyl group” as used throughout the presentspecification refers to a substituent wherein a carbonyl group is bondedto the aforementioned “C₁₋₆ alkoxy group”, and as specific examplesthere may be mentioned ethoxycarbonyl, n-propoxycarbonyl,i-propoxycarbonyl, sec-propoxycarbonyl, n-butoxycarbonyl,i-butoxycarbonyl, 1,2-dimethylpropoxycarbonyl and2-ethylpropoxycarbonyl.

The term as used throughout the present specification indicates a normaltype or primary substituent, “sec-” indicates a secondary substituent,“t-” indicates a tertiary substituent and “i-” indicates an iso typesubstituent.

The term “C₁₋₆ alkylenedioxy group” as used throughout the presentspecification refers to a substituent having oxygen atoms at each end ofa divalent group derived by removing one more hydrogen atom from a “C₁₋₆alkyl group”, and as specific examples there may be mentionedmethylenedioxy, ethylenedioxy, propylenedioxy, butylenedioxy,pentylenedioxy and hexylenedioxy.

The term “C₆₋₁₄ aryl group” as used throughout the present specificationrefers to an aromatic ring group of 6 or 14 carbons, and as specificexamples there may be mentioned benzene, pentalene, indene, naphthalene,azulene, heptalene, biphenylene, indacene, acenaphthylene, fluorene,phenalene, phenanthrene and anthracene, and preferably benzene,pentalene, indene, naphthalene and azulene.

The term “hetero atom” as used throughout the present specificationrefers to, specifically, an oxygen atom, sulfur atom, nitrogen atom,phosphorus, arsenic, antimony, silicon, germanium, tin, lead, boron,mercury or the like, and preferably an oxygen atom, sulfur atom ornitrogen atom.

The term “5- to 14-membered aromatic heterocyclic group” as usedthroughout the present specification refers to an aromatic cyclic grouphaving 5 to 14 atoms forming the cyclic ring and including at least onehetero atom such as nitrogen, sulfur or oxygen among the atoms formingthe cyclic ring. As specific examples there may be mentionednitrogen-containing aromatic heterocycles such as pyrrole, pyridine,pyridone, pyridazine, pyrimidine, pyrazine, pyrazole, imidazole,triazole, tetrazole, indole, isoindole, indolizine, purine, indazole,quinoline, isoquinoline, quinolizine, phthalazine, naphthyridine,quinoxaline, quinazoline, cinnoline, pteridine, imidazopyridine,imidazotriazine, pyrazinopyridazine, acridine, phenanthridine,carbazole, carbazoline, perimidine, phenanthroline, phenacene,oxadiazole, benzimidazole, pyrrolopyridine, pyrrolopyrimidine andpyridopyrimidine; sulfur-containing aromatic heterocycles such asthiophene and benzothiophene; oxygen-containing aromatic heterocyclessuch as furan, pyran, cyclopentapyran, benzofuran and isobenzofuran; andaromatic heterocycles comprising 2 or more hetero atoms selected fromamong nitrogen, sulfur and oxygen, such as thiazole, thiadizole,isothiazole, benzoxazole, benzothiazole, benzothiadiazole,phenothiazine, isoxazole, furazan, phenoxazine, pyrazoloxazole,imidazothiazole, thienofuran, furopyrrole, pyridoxazine, furopyridine,furopyrimidine, thienopyrimidine and oxazole. As examples of the “5- to14-membered aromatic heterocyclic group” there may be mentionedpreferably, pyridine, pyridone, pyrimidine, imidazole, indole,quinoline, isoquinoline, quinolizine, phthalazine, naphthyridine,quinazoline, cinnoline, acridine, phenacene, thiophene, benzothiophene,furan, pyran, benzofuran, thiazole, benzthiazole, phenothiazine,pyrrolopyrimidine, furopyridine and thienopyrimidine, more preferablypyridine, thiophene, benzothiophene, thiazole, benzothiazole, quinoline,quinazoline, cinnoline, pyrrolopyrimidine, pyrimidine, furopyridine andthienopyrimidine.

The term “5- to 14-membered non-aromatic heterocyclic group” as usedthroughout the present specification refers to a non-aromatic cyclicgroup having 5 to 14 atoms forming the cyclic ring and including atleast one hetero atom such as nitrogen, sulfur or oxygen among the atomsforming the cyclic ring. As specific examples there may be mentionednon-aromatic heterocycles such as pyrrolidinyl, pyrrolinyl, piperidinyl,piperazinyl, N-methylpiperazinyl, imidazolinyl, pyrazolidinyl,imidazolidinyl, morpholinyl, tetrahydropyranyl, azetidinyl, oxetanyl,oxathiolanyl, pyridone, 2-pyrrolidone, ethyleneurea, 1,3-dioxolane,1,3-dioxane, 1,4-dioxane, phthalimide and succinimide. As examples ofthe “5- to 14-membered non-aromatic heterocyclic group” there may bementioned preferably, pyrrolidinyl, piperidinyl and morpholinyl, andmore preferably pyrrolidinyl, piperidinyl, morpholinyl and pyrrole.

The term “5- to 14-membered heterocyclic group” as used throughout thepresent specification refers to an aromatic or non-aromatic cyclic grouphaving 5 to 14 atoms forming the cyclic ring and including at least onehetero atom such as nitrogen, sulfur or oxygen among the atoms formingthe cyclic ring, which is a “5- to 14-membered aromatic heterocyclicgroup” in the former case and a “5- to 14-membered non-aromaticheterocyclic group” in the latter case. Specific examples of the “5- to14-membered heterocyclic group” therefore include specific examples ofthe “5- to 14-membered aromatic heterocyclic group” and specificexamples of the “5- to 14-membered non-aromatic heterocyclic group”.

As the “5- to 14-membered heterocyclic group” there may be mentionedpreferably pyrrolidinyl, piperidinyl, morpholinyl, pyrrole, pyridine,pyridone, pyrimidine, imidazole, indole, quinoline, isoquinoline,quinolizine, phthalazine, naphthyridine, quinazoline, cinnoline,acridine, phenacene, thiophene, benzothiophene, furan, pyran,benzofuran, thiazole, benzothiazole, phenothiazine and carbostyryl, morepreferably pyrrolidinyl, piperidinyl, morpholinyl, pyrrole, pyridine,thiophene, benzothiophene, thiazole, benzothiazole, quinoline,quinazoline, cinnoline and carbostyryl, and even more preferablythiazole, quinoline, quinazoline, cinnoline and carbostyryl.

The term “6- to 14-membered aromatic heterocyclic group” as usedthroughout the present specification refers to those substituentsdefined by “5- to 14-membered aromatic heterocyclic group” which have 6to 14 atoms forming the cyclic ring. As specific examples there may bementioned pyridine, pyridone, pyrimidine, indole, quinoline,isoquinoline, quinolizine, phthalazine, naphthyridine, quinazoline,cinnoline, acridine, benzothiophene, benzofuran, thiazole, benzothiazoleand phenothiazine.

The term “6- to 14-membered heterocyclic group” as used throughout thepresent specification refers to those substituents defined by “5- to14-membered heterocyclic group” which have 6 to 14 atoms forming thecyclic ring. As specific examples there may be mentioned piperidinyl,piperazinyl, N-methylpiperazinyl, morpholinyl, tetrahydropyranyl,1,4-dioxane and phthalimide.

The term “C₆₋₁₄ aryl-C₁₋₆ alkyl group [=aralkyl group]” as usedthroughout the present specification refers to a “C₁₋₆ alkyl group”substituted at substitutable positions with a “C₆₋₁₄ aryl group”, and asspecific examples there may be mentioned benzyl, phenethyl,3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 6-phenylhexyl,1-naphthylmethyl, 2-naphthylmethyl, 1-naphthylethyl, 2-naphthylethyl,1-naphthylpropyl and 2-naphthylpropyl, preferably benzyl, phenethyl,3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 6-phenylhexyl,1-naphthylmethyl, 2-naphthylmethyl, 1-naphthylethyl, 2-naphthylethyl,1-naphthylpropyl and 2-naphthylpropyl, more preferably benzyl,phenethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 6-phenylhexyl,1-naphthylmethyl, 2-naphthylmethyl, even more preferably benzyl,phenethyl, 3-phenylpropyl, 4-phenylbutyl, and most preferably benzyl andphenethyl.

The term “5- to 14-membered heterocyclic-C₁₋₆ alkyl group” as usedthroughout the present specification refers to a “C₁₋₆ alkyl group”substituted at substitutable positions with a “5- to 14-memberedheterocyclic group”, and as specific examples there may be mentioned2-pyridylmethyl, 3-pyridylmethyl and 2-quinolinomethyl.

A “leaving group” in the sense used throughout the present specificationmay be any group commonly known as a leaving group in chemicalsynthesis, with no special restrictions, and as specific examples theremay be mentioned halogen atoms such as chlorine, bromine and iodine;alkylthio groups such as methylthio, ethylthio and propylthio; arylthiogroups such as phenylthio, toluylthio and 2-pyridylthio;alkylsulfonyloxy groups such as methanesulfonyloxy,trifluoromethanesulfonyloxy, ethanesulfonyloxy and propanesulfonyloxy;arylsulfonyloxy groups such as benzenesulfonyloxy andp-toluenesulfonyloxy; alkanoyloxy groups such as acetoxy andtrifluoroacetoxy; alkoxy groups such as methoxy, ethoxy and propoxy;alkylamino groups such as methylamino, ethylamino, propylamino andbutylamino; dialkylamino groups such as dimethylamino, diethylamino,dipropylamino, methylethylamino, ethylpropylamino and methylpropylamino;and substituted phosphoryloxy groups such as diphenoxyphosphoryloxy.Preferred are halogen atoms such as chlorine, bromine and iodine, andtrifluoromethanesulfonyloxy.

The term “optionally substituted” as used throughout the presentspecification is synonymous with “optionally having one or moresubstituents in any desired combination at substitutable positions”, andas specific examples of substituents there may be mentioned (1)halogens, (2) hydroxyl, (3) thiol, (4) nitro, (5) nitrile, (6) oxo, (7)azido, (8) guanidino, (9) hydrazino, (10) isocyano, (11) cyanate, (12)isocyanate, (13) thiocyanate, (14) isothiocyanate, (15) nitroso, (16)carbamido(ureido), (17) formyl, (18) C₁₋₆ imidoyl, (19) optionallyhalogenated or hydroxylated C₁₋₆ alkyl groups, C₂₋₆ alkenyl groups, C₂₋₆alkynyl groups, C₃₋₆ cycloalkyl groups, C₃₋₆ cycloalkenyl groups, C₃₋₆cycloalkynyl groups, C₁₋₆ alkoxy groups, C₂₋₆ alkenyloxy groups, C₂₋₆alkynyloxy groups, C₃₋₈ cycloalkoxy groups, C₁₋₆ alkylthio groups, C₂₋₆alkenylthio groups, C₂₋₆ alkynylthio groups, C₃₋₆ cycloalkylthio groupsor C₁₋₆ alkylenedioxy groups, (20) C₆₋₁₄ aryl groups, (21) 5- to14-membered heterocyclic groups, (22) carboxyl, (23) trifluoromethyl,(24) C₆₋₁₄ aryl-C₁₋₆ alkyl groups, (25) 5- to 14-membered heterocyclicC₁₋₆ alkyl groups or (26) the group represented by the formula—V^(XX1)—V^(XX2)—V^(XX3)—V^(XX4) (wherein V^(XX1), V^(XX2) and V^(XX3)are each independently 1) a single bond, 2) oxygen, 3) sulfur, 4) —CO—,5) —SO—, 6) —SO₂—, 7) —NR^(XX1)—, 8) —CONR^(XX1)—, 9) —NR^(XX21)CO—, 10)—SO₂NR^(XX1)—, 11) —NR^(XX1)SO₂—, 12) —O—CO—, 13) —C(O)O—, 14)—NR^(XX1)C(O)O—, 15) —NR^(XX1)C(O)NR^(XX2)—, 16) —O—C(O)NR^(XX1)—, 17)—O—C(O)O—, 18) a C₁₋₆ alkylene group, 19) a C₂₋₆ alkenyl group, 20) aC₂₋₆ alkynyl group, 21) a C₃₋₈ alicyclic hydrocarbon group, 22) a C₆₋₁₄aryl group, 23) a 5- to 14-membered heterocyclic group or 24) a 5- to14-membered aromatic heterocyclic group; and V^(XX4), R^(XX1) andR^(XX2) are each independently 1) hydrogen, 2) a C₁₋₆ alkyl group, 3) aC₂₋₆ alkenyl group, 4) a C₂₋₆ alkynyl group, 5) a C₃₋₈ alicyclichydrocarbon group, 6) a C₆₋₁₄ aryl group, 7) a 5- to 14-memberedheterocyclic group, 8) a 5- to 14-membered aromatic heterocyclic groupor 9) a C₁₋₆ alkoxy group.)

Thus, “optionally substituted” means optionally substituted with asubstituent, specific examples of which are hydroxyl; thiol; nitro;morpholino; thiomorpholino; halogens such as fluorine, chlorine, bromineand iodine; nitrile; azide; formyl; alkyl groups such as methyl, ethyl,propyl, isopropyl and butyl; alkenyl groups such as vinyl, allyl andpropenyl; alkynyl groups such as ethynyl, butynyl and propargyl, alkoxygroups corresponding to lower alkyl groups, such as methoxy, ethoxy,propoxy and butoxy; halogenoalkyl groups such as fluoromethyl,difluoromethyl, trifluoromethyl and fluoroethyl; hydroxyalkyl groupssuch as hydroxymethyl, hydroxyethyl and hydroxypropyl; guanidino;formimidoyl; acetoimidoyl; carbamoyl; thiocarbamoyl; carbamoylalkylgroups such as carbamoylmethyl and carbamoylethyl; alkylcarbamoyl groupssuch as methylcarbamoyl and dimethylcarbamoyl; carbamide; alkanoylgroups such as acetyl; amino; alkylamino groups such as methylamino,ethylamino and isopropylamino; dialkylamino groups such asdimethylamino, methylethylamino and diethylamino; aminoalkyl groups suchas aminomethyl, aminoethyl and aminopropyl; carboxy; alkoxycarbonylgroups such as methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl;alkoxycarbonylalkyl groups such as methoxycarbonylmethyl,ethoxycarbonylmethyl, propoxycarbonylmethyl, methoxycarbonylethyl,ethoxycarbonylethyl and propoxycarbonylethyl; alkyloxyalkyl groups suchas methyloxymethyl, methyloxyethyl, ethyloxymethyl and ethyloxyethyl;alkylthioalkyl groups such as methylthiomethyl, methylthioethyl,ethylthiomethyl and ethylthioethyl; aminoalkylaminoalkyl groups such asaminomethylaminomethyl andaminoethylaminomethyl; alkylcarbonyloxy groupssuch as methylcarbonyloxy, ethylcarbonyloxy and isopropylcarbonyloxy;arylalkoxyalkoxyalkyl groups such as oxymethyl andbenzyloxyethyloxyethyl; hydroxyalkoxyalkyl groups such ashydroxyethyloxymethyl and hydroxyethyloxyethyl; arylalkoxyalkyl groupssuch as benzyloxymethyl, benzyloxyethyl and benzyloxypropyl; quaternaryammonio groups such as trimethylammonio, methylethylmethylammonio andtriethylammonio; cycloalkyl groups such as cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl; cycloalkenyl groups such as cyclopropenyl,cyclobutenyl, cyclopentenyl and cyclohexenyl; aryl groups such asphenyl, pyridinyl, thienyl, furyl and pyrrolyl; alkylthio groups such asmethylthio, ethylthio, propylthio and butylthio; arylthio groups such asphenylthio, pyridinylthio, thienylthio, furylthio and pyrrolylthio; aryllower alkyl groups such as benzyl, trityl and dimethoxytrityl;substituted sulfonyl groups such as sulfonyl, mesyl andp-toluenesulfonyl; aroyl groups such as benzoyl; halogenoaryl groupssuch as fluorophenyl and bromophenyl; and oxyalkoxy groups such asmethylenedioxy.

The term “C₁₋₆ imidoyl group” as used throughout the presentspecification refers to, for example, formimidoyl, hexaneimidoyl,succinimidoyl, or the like.

Throughout the present specification, when ring A is a 5- to 14-memberedheterocyclic group, it is preferably one selected from among pyridine,pyrimidine, pyridopyrimidine, isoquinoline, phthalazine, quinoline,quinazoline, pyrimidopyrimidine, quinoxaline, pyridopyridine,pyrrolopyridine, pyrrolopyrimidine, indole, pyrazolopyridine,pyrazolopyrimidine, thienopyridine, thienopyrimidine, benzothiazole,thiazolopyridine, thiazolopyrimidine, benzimidazole, imidazopyridine,imidazopyrimidine, thiazole, imidazole, pyrazole, benzofuran,furopyridine, furopyrimidine, benzoxazole, oxazolopyridine,oxazolopyrimidine, pyridopyrimidin-7-one, pyrazine, pyridazine,pyridone, pyrimidone, oxyindole, pyrazoloquinazoline, pyrazoloquinoline,pyrroloquinazoline, pyrroloquinoline, isoindolin-1-one,isoazaindolin-1-one, isoflavone, benzopyran-4-one, benzimidazolin-2-one,1,3-dioxo-1,3-dihydroisoindole, 2,3-dihydro-pyrrolopyridin-2-one,2,3-dihydro-pyrroloquinolin-2-one, imidazol-2-one, benzene, naphthalene,oxazole, isoxazole, isothiazole and quinazolin-4-one. There may bementioned as preferred groups, quinoline, pyridine, pyrrolopyrimidine,pyrimidine, quinazoline, pyridopyridine, pyridopyrimidine,pyrazolopyrimidine, thiazolopyridine, furopyridine and thienopyrimidine,and as more preferred groups, quinoline, pyridine, pyrrolopyrimidine,thienopyrimidine, pyrimidine and furopyridine, although there is nolimitation to these.

In cases where Y is a group with a hetero atom, such as a 5- to14-membered heterocyclic group, the invention naturally encompassescompounds wherein a substituent such as X or T^(g1) is bonded at thehetero atom.

Production methods for the compounds of the invention will now bedescribed. Various methods may be imagined for production of compoundsof the invention represented by general formulas (I) and (II) withsynthesis carried out by ordinary chemical synthesis means, and thefollowing are representative examples of methods for their production.

[Representative Production Methods]

[Production Method 1]

In formula (a-01), U represents a leaving group. The other symbols havethe same definitions as above.

The leaving group may be, for example, a halogen or atrifluoromethanesulfonyl group. There are no particular restrictions onthe solvent used for the reaction, though it is preferably one with lowreactivity for the starting materials, and as examples there may bementioned 1-methylpyrrolidone, dimethylformamide, chlorbenzene, and thelike. An organic or inorganic base may also be added.

The reaction time may be from 10 minutes to 30 hours, and the reactiontemperature from room temperature to reflux temperature.

In the following formulas for the representative production methods Z,R³⁰⁰, R³⁰¹, W, W¹¹, R¹, R² and Y have the same definitions as above;X^(sa1) is an oxygen or sulfur atom; R^(sa4) has the same definition asR² above; R^(sa5) is an optionally substituted C₁₋₆ alkyl group oroptionally substituted C₆₋₁₄ aryl group; compound (a-6) is compound(a-61) or compound (a-62); R^(sa70) is an optionally substituted C₁₋₆alkyl group; G₁ is an optionally substituted nitrogen atom or oxygenatom; U is a leaving group; n and s are each integers of 0 to 6;R^(sa90) is a nitro or amino group; R^(sa82) is an amino-protectinggroup such as t-butoxycarbonyl or benzyl; and R^(sa1), R^(sa2), R^(sa3),R^(sa50), R^(sa60), R^(sa71) and R^(sa80) independently are defined assubstituents selected from among the substituents for ring A mentionedabove.

[Production Method 2-1]

Representative production method for compound (G2) represented by:

(wherein the symbols have the same definitions given above):

(wherein the symbols have the same definitions given above.)

(wherein the symbols have the same definitions given above.)<Step A-1> <Step A-2>

Steps of cyclization from an aniline derivative (a-1) to a quinolonederivative (a-3). The synthesis may be carried out by the known methodreported in Tetrahedron, 53, 1743(1997).

<Step A-1>

Specifically, an aniline derivative having any desired substituents(a-1) may be reacted with an orthoester derivative such as trimethylorthoformate or triethyl orthoformate and Meldrum acid in an alcoholsuch as ethanol to obtain compound (a-2). The reaction temperature maybe from room temperature to reflux temperature, and the reaction timefrom 10 minutes to 30 hours.

<Step A-2>

Compound (a-2) is then heated in a mixed solvent of phenyl ether,biphenyl, etc. or Dowtherm A to obtain compound (a-3). The reactiontemperature may be from 40° C. to reflux temperature, and the reactiontime from 10 minutes to 30 hours.

<Step A-3>

Chlorination step. Compound (a-3) may be reacted with a chlorinatingagent such as phosphorus oxychloride or thionyl chloride to obtaincompound (a-4). The reaction solvent used may be phosphorus oxychloride,thionyl chloride, benzene, toluene or the like, the reaction temperaturefrom room temperature to reflux temperature, and the reaction time from10 minutes to 30 hours.

<Step A-4>

Step of reacting compound (a-4) with compound (a-42) to obtain a nitrocompound (a-5). The reaction solvent may be 1-methylpyrrolidone,dimethylformamide, chlorbenzene, 2,6-lutidine, or the like. The reactionmay be conducted with addition of a base, for example, an organic basesuch as diisopropylethylamine or 2,6-lutidine, or an inorganic base suchas potassium carbonate. The reaction time may be from 10 minutes to 30hours and the reaction temperature from room temperature to refluxtemperature.

<Step A-42>

Step of reacting compound (a-4) with compound (a-43) to obtain an aminocompound (a-61). The reaction solvent used may be 1-methylpyrrolidone,dimethylsulfoxide, or the like. A base such as sodium hydride may beused for the reaction. The reaction time may be from 10 minutes to 30hours and the reaction temperature from room temperature to refluxtemperature.

<Step A-5>

Step of reduction reaction of the nitro compound (a-5) to an aminocompound (a-61). This may be carried out under conditions commonlyemployed for reduction of nitro groups to amino groups. Specifically,there may be mentioned reduction with iron-ammonium chloride,iron-hydrochloric acid or iron-acetic acid, or catalytic reduction withpalladium hydroxide-hydrogen. The reaction solvent may be methanol,ethanol, tetrahydrofuran, dimethylformamide or the like, and catalyticreduction may be conducted at ordinary pressure or under pressurization.The reaction time may be from 10 minutes to 30 hours and the reactiontemperature from room temperature to reflux temperature.

<Step A-6>

Step of alkylation of the amino compound (a-61). The amino compound(a-61) may be reacted with an aldehyde derivative or ketone derivativeand the resultant imine reduced with a reducing agent such as sodiumcyanoborohydride to obtain compound (a-62).

Alternatively, the amino compound (a-61) may be reacted with an acidchloride derivative or acid anhydride in the presence of a base and thenreduced with a reducing agent such as lithium aluminum hydride to obtaincompound (a-62).

<Step A-7>

Step of reacting a carbamate derivative (a-81) with the amino derivative(a-61) or compound (a-62) to obtain a urea derivative (a-10). Thereaction solvent used may be chloroform, toluene, acetonitrile,dimethylformamide, dimethylsulfoxide or the like. The reaction time maybe from 10 minutes to 30 hours and the reaction temperature from belowfreezing to reflux temperature. The reaction may also be conducted withaddition of an organic base such as sodium hydride, triethylamine orpyridine or an inorganic base such as potassium carbonate or sodiumcarbonate.

<Step A-8>

Step of reacting an isocyanate derivative (a-82) with the aminoderivative (a-61) or compound (a-62) to obtain compound (a-7). Thereaction solvent used may be chloroform, toluene, acetonitrile,dimethylformamide, dimethylsulfoxide or the like. The reaction time maybe from 10 minutes to 30 hours and the reaction temperature from belowfreezing to reflux temperature. The reaction may also be conducted withaddition of an organic base such as sodium hydride, triethylamine orpyridine or an inorganic base such as potassium carbonate or sodiumcarbonate.

<Step A-9>

Step of reacting compound (a-7) and compound (a-83) in the presence of abase such as pyridine to obtain a urea derivative (a-10). The reactionsolvent used may be dimethylsulfoxide, dimethylformamide,tetrahydrofuran or the like, the reaction time from 10 minutes to 30hours and the reaction temperature from 0° C. to reflux temperature.

<Step A-10>

Step of reacting a carbamating reagent (a-84) such asphenylchloroformate with the amino compound (a-61) or compound (a-62) toobtain a carbamate derivative (a-9). The reaction may be conducted usinga base such as pyridine. The reaction solvent used may bedimethylsulfoxide, dimethylformamide, tetrahydrofuran or the like, thereaction time from 10 minutes to 30 hours, and the reaction temperaturefrom 0° C. to reflux temperature.

<Step A-11>

Step of reacting an amine derivative (a-85) with the carbamatederivative (a-9) to obtain a urea derivative (a-10). The reaction may beconducted using a base such as triethylamine. The reaction solvent usedmay be dimethylsulfoxide, dimethylformamide or the like, the reactiontime from 10 minutes to 30 hours, and the reaction temperature from roomtemperature to reflux temperature.

[Production Method 2-2]

Alternative production method to compound (a-10):

(wherein the symbols have the same definitions given above.)<Step A-12>

Step of reacting a phenol derivative (a-12) having urea as a part of itsstructure, with a 4-chloroquinoline derivative (a-4) to obtain thetarget compound (a-11) by one direct step. The reaction solvent used maybe 1-methylpyrrolidone, dimethylformamide, chlorbenzene, or the like.The reaction may be conducted with addition of a suitable base, forexample, an organic base such as diisopropylethylamine, or an inorganicbase such as potassium carbonate or sodium hydride. The reaction timemay be from 10 minutes to 30 hours and the reaction temperature fromroom temperature to reflux temperature.

[Production Method 2-3]

Alternative production method to compound (a-5) and compound (a-61):

(wherein the symbols have the same definitions given above.)<Step 2A-1>

Step of reacting a pyridine derivative (2a-1) with compound (a-5) toobtain compound (2a-2). The reaction may be conducted using a base suchas potassium carbonate. The reaction solvent used may bedimethylformamide or the like, the reaction time from 10 minutes to 30hours and the reaction temperature from room temperature to refluxtemperature.

<Step 2A-2>

Step of converting a quinolone (a-5) to a thioquinolone (2a-3). Asulfide reagent such as sodium sulfide, phosphorus pentasulfide or thelike may be reacted with the quinolone (a-5) to obtain the correspondingthioquinolone. The reaction solvent used may be diglyme, the reactiontemperature from room temperature to reflux temperature, and thereaction time from 10 minutes to 30 hours.

<Step 2A-3>

Step of reacting the thioquinolone (2a-3) with compound (2a-4) to obtaincompound (2a-5). The reaction solvent used may be dimethylformamide orthe like, the reaction temperature from room temperature to refluxtemperature, and the reaction time from 10 minutes to 30 hours. Anappropriate base such as pyridine may also be used.

(wherein the symbols have the same definitions given above.)<Step 2A-4>

Step of reacting a hydroxypyridine derivative (2a-6) with compound (a-4)to obtain compound (2a-7). The solvent used may be 1-methylpyrrolidone,dimethylformamide, chlorbenzene, or the like. The reaction may beconducted with addition of a suitable base, for example, an organic basesuch as diisopropylethylamine, or an inorganic base such as potassiumcarbonate. The reaction time may be from 10 minutes to 30 hours, and thereaction temperature from room temperature to reflux temperature.

<Step 2A-5>

Step of palladium coupling reaction between compound (2a-7) and an iminederivative to obtain compound (2a-8). The reaction may be conductedusing a solvent such as toluene, a catalyst, for example, a palladiumderivative such as tris(dibenzylideneacetone)dipalladium(0) or aphosphine derivative such as2,2′-bis(diphenylphosphino)-1,1′-binaphthyl), and a base such ast-butoxypotassium. The reaction temperature may be from about 50° C. toreflux temperature, and the reaction time from about 1 hour to 10 hours.

<Step 2A-6>

Step of obtaining an amino derivative (2a-9) from compound (2a-8). Thereaction is conducted using ethanol, water or the like, with the actionof an acid such as hydrochloric acid. The reaction temperature may befrom 0° C. to about 100° C., and the reaction time from 10 minutes toabout 10 hours.

<Step 2A-7>

Step of dechlorination of compound (2a-9) to obtain compound (2a-10).This may be accomplished by catalytic reduction or the like usingpalladium carbon-hydrogen. The reaction solvent may be methanol,ethanol, tetrahydrofuran, or the like, and catalytic reduction may beconducted at ordinary pressure or under pressurization. Triethylamine orthe like may also be used as a base. The reaction time may be from 10minutes to 30 hours and the reaction temperature from room temperatureto reflux temperature.

(wherein the symbols have the same definitions given above.)<Step 2A-8>

A step of converting a quinolone compound (a-3) into a4-aminoalkoxyquinoline (2a-11). An N-alkylphthalimide derivative may bereacted with compound (a-3) and deprotection accomplished with hydrazinehydrate or the like to obtain the target compound (2a-11). The solventused may be dimethylformamide, tetrahydrofuran or the like, the reactiontemperature from room temperature to reflux temperature, and thereaction time from 10 minutes to 30 hours. Potassium carbonate or thelike may also be used as the base.

[Production Method 2-4]

Alternative production method to compound (a-4):

(wherein the symbols have the same definitions given above.)<Step 3A-1>

Step of obtaining an enamine (3a-1). Diethyl ethoxymethylenemalonate maybe reacted with an aniline derivative (a-1) to obtain compound (3a-1).The reaction proceeds without a solvent. The reaction temperature may beabout 100° C., and the reaction time from 30 minutes to several hours.

<Step 3A-2>

Step of cyclization. Compound (3a-1) may be heated from about 200° C. toabout 260° C. in a biphenyl ether/biphenyl mixed solvent for cyclizationto obtain the target compound (3a-2). The reaction time may be from 30minutes to 10 hours.

<Step 3A-3>

Step of chlorination. The same procedure as in <Step A-3> may be carriedout to obtain the chlorinated compound (3a-3) from compound (3a-2).

[Production Method 3]

Representative production method for compound (G3) represented by:

(wherein the symbols have the same definitions given above)

(wherein the symbols have the same definitions given above.)<Step B-1>

Step of reacting compound (a-4) with an indole derivative (b-2) toobtain compound (b-1). The reaction may be conducted under the sameconditions as for <Step A-4> above.

<Step B-2>

Step of obtaining a urea derivative (b-3) from compound (b-1). Thereagent used may be the aforementioned isocyanate derivative (a-82) orcarbamate derivative (a-81). The reaction may be conducted under thesame conditions as for <Step A-7>, <Step A-8> and <Step A-9> above.

(wherein the symbols have the same definitions given above.)<Step B-3>

Step of introducing a substituent at the 3-position of the indole.Compound (b-4) may be reacted with a halogenating agent such asN-chlorosuccinimide or N-bromosuccinimide, or with phosphorusoxychloride or a thionyl chloride/dimethylformamide mixed reagent toobtain compound (b-5). The reaction solvent used may be 2-propanol,tetrahydrofuran, acetonitrile, dimethylformamide or the like, thereaction temperature from 0° C. to reflux temperature, and the reactiontime from 10 minutes to 30 hours.

[Production Method 4-1]

Representative production method for compound (G4-1) represented by:

(wherein the symbols have the same definitions given above)

(wherein the symbols have the same definitions given above.)

General formula (G4-1) may be synthesized according to the processdescribed in WO97/02266, PCT/EP96/02728 or Journal of MedicinalChemistry, 1996, Vol. 39, No. 12, 2285-2292.

<Step C-1>

Step of synthesizing an imidate. Ethyl cyanoacetate may be reacted withhydrochloric acid in a solvent such as dioxane to obtain the targetimidate compound (c-2). The reaction temperature is preferably from near0° C. to room temperature, and the reaction time may be from a few hoursto several days.

<Step C-2>

Step of synthesizing an amidine. Compound (c-2) may be reacted withammonia gas in ethanol to obtain the target amidine compound (c-3). Thereaction temperature may be from near 0° C. to room temperature, and thereaction time may be several hours.

<Step C-3>

Step of synthesizing a pyrrole derivative. Compound (c-3) may be reactedwith an α-haloketone derivative (c-31) in ethanol to obtain the targetpyrrole derivative (c-4). The reaction temperature may be from roomtemperature to reflux temperature, and the reaction time from a fewhours to several days.

<Step C-4>

Ring-closing reaction of pyrrole ring to pyrrolopyrimidine ring.Compound (c-4) may be reacted with formamide and formic acid to obtainthe target compound (c-5). The solvent used may be dimethylformamide.The reaction temperature may be from near 100° C. to reflux temperature,and the reaction time from a few hours to several days.

<Step C-5>

Step of chlorination. The same procedure as in <Step A-3> may be carriedout to obtain the target chlorinated compound (c-6).

(wherein the symbols have the same definitions given above.)<Step C-6>

Reaction for introduction of substituent at 5-position of a pyrrolederivative (c-70). Compound (c-70) may be reacted with compound (c-71)in the presence of 2,6-lutidine, in darkness under a nitrogenatmosphere, to obtain the target compound (c-8). The reaction solventused may be dichloromethane or the like, the reaction temperature from0° C. to room temperature, and the reaction time from 1 hour to 30hours.

<Step C-7>

The same procedure as in <Step C-4> may be carried out to obtaincompound (c-9).

<Step C-8>

The same procedure as in <Step A-3> may be carried out to obtaincompound (c-10).

[Production Method 4-2]

Representative production method for compound (G4-2) represented by:

(wherein the symbols have the same definitions given above.)

(wherein the symbols have the same definitions given above.)<Step 2C-1>

Step of chlorination. Compound (2c-1) may be reacted with thionylchloride to obtain the target compound (2c-2). The reaction solvent usedmay be thionyl chloride, the reaction temperature may be refluxtemperature, and the reaction time from a few hours to several days.

<Step 2C-2>

Rearrangement from carboxylic acid to a carbamate derivative (2c-3). Thecarboxylic acid derivative (2c-2) may be reacted with tert-butanol,benzyl alcohol, trimethylsilyl alcohol or the like in the presence ofdiphenylphosphoryl azide and triethylamine to obtain the targetcarbamate derivative (2c-3). The reaction solvent used may betert-butanol, benzyl alcohol, dimethylformamide, toluene or the like,the reaction temperature from room temperature to reflux temperature,and the reaction time from 10 minutes to 30 hours.

<Step 2C-3>

Iodination reaction. The target compound (2c-4) may be obtained by usinga base to generate an anion at the 3-position of pyridine, reactingiodine therewith to obtain an iodinated compound, and then conductingdecarbamating reaction. The reaction solvent for the iodination may betetrahydrofuran, diethyl ether or the like, the reaction temperaturefrom −78° C. to room temperature, and the reaction time from 10 minutesto 30 hours. The base used may be n-butyllithium or the like, and a basesuch as N,N,N′,N′-tetramethylethenediamine may also be added asappropriate. The reaction solvent used for the decarbamating reactionmay be water, an alcohol or the like, as an acid there may be usedaqueous hydrobromic acid, aqueous hydrochloric acid or the like, thereaction temperature may be from room temperature to reflux temperature,and the reaction time may be from 1 minute to several hours.

<Step 2C-4>

The same procedure as in <Step A-4> may be carried out to obtain thetarget compound (2c-5).

<Step 2C-5>

Coupling reaction between the iodo compound (2c-5) and an acetylenederivative. The iodo compound may be reacted with (trimethyl)acetylenein the presence of tetrakis(triphenylphosphine)palladium,copper(I)iodide or the like to obtain the target compound (2c-6). Thereaction solvent used may be dimethylformamide or the like, the reactiontemperature from room temperature to reflux temperature, and thereaction time from 10 minutes to 30 hours.

<Step 2C-6>

Cyclization reaction. Compound (2c-6) may be heated in the presence ofcopper (I) iodide to obtain the target cyclized compound (2c-7). Thereaction solvent used may be dimethylformamide or the like, the reactiontemperature from 80° C. to reflux temperature, and the reaction timefrom 5 minutes to 10 hours.

[Production Method 4-3]

Alternative production method to compound (2c-7) in Production Method4-2:

(wherein the symbols have the same definitions given above.)<Step 2C-7>

Conversion of ketone (2c-8) to thioketone (2c-90). Synthesis may becarried out by the same procedure as in <Step 2A-2).

<Step 2C-8>

Synthesis may be carried out by the same procedure as in <Step 2A-3>.

[Production Method 5-1]

Representative production method for compound (G5-1) represented by:

(wherein the symbols have the same definitions given above.)

(wherein the symbols have the same definitions given above.)<Step D-1>

The same procedure as in <Step A-4> may be carried out to obtain thetarget compound (d-2).

<Step D-2>

Step of amination of chloro group. The 2-chloropyrimidine derivative(d-2) may be reacted with ammonia to obtain the target amino compound(d-3). The reaction solvent used may be ethanol, tetrahydrofuran or thelike, the reaction temperature from 0° C. to reflux temperature, and thereaction time from 10 minutes to 30 hours.

<Step D-3>

Reduction of nitro compound (d-3) to amino compound (d-4). The sameprocedure as in <Step A-5> may be carried out to obtain the target aminocompound (d-4).

<Step D-4>

The same procedure as in <Step A-7> may be carried out to obtain thetarget urea compound (d-5).

(wherein the symbols have the same definitions given above.)<Step D-6>

The same procedure as in <Step A-4> may be carried out to obtain thetarget compound (d-8).

<Step D-7>

Step of dechlorination and nitro group reduction. The target compound(d-9) may be obtained under common catalytic reduction conditions withpalladium hydroxide-hydrogen or the like. The reaction solvent used maybe methanol, ethanol, tetrahydrofuran, dimethylformamide or the like,and catalytic reduction may be conducted at ordinary pressure or underpressurization. The reaction time may be from 10 minutes to 30 hours andthe reaction temperature from room temperature to reflux temperature.

<Step D-8>

The same procedure as in <Step A-7> may be carried out to obtain thetarget urea compound (d-10).

[Production Method 5-2]

Representative production method for compound (G5-2) represented by:

(wherein the symbols have the same definitions given above.)

(wherein the symbols have the same definitions given above.)<Step 2D-1>

Decarbamating reaction. Compound (2d-1) may be reacted with an acid toobtain the target amine derivative (2d-2). The solvent used may bewater, dioxane, tetrahydrofuran, methanol, ethanol or the like, thereaction temperature from room temperature to reflux temperature and thereaction time from 10 minutes to 30 hours. The acid used may behydrochloric acid, hydrobromic acid, trifluoroacetic acid, or the like.

<Step 2D-2>

Compound (2d-2) may be used in the same procedure from <Step D-6> to<Step D-8> of Production Method 5-1 to obtain a urea derivative (2d-3).

[Production Method 6]

Alternative production method for compounds (G6-1), (G6-2) and (G6-3)represented by:

(wherein the symbols have the same definitions given above.)

(wherein the symbols have the same definitions given above.)<Step E-1>

Coupling reaction between iodo compound and ethyl acrylate. Compound(e-1) may be reacted with ethyl acrylate in the presence of a catalystsuch as palladium acetate and a tertiary amine such as tributylamine, toobtain the target compound (e-2). The reaction solvent used may bedimethylformamide or the like, the reaction temperature from 100° C. toreflux temperature, and the reaction time from 5 minutes to 30 hours.

<Step E-2>

Reduction of double bond, followed by cyclization and nitro groupreduction. Compound (e-2) may be reacted in the presence of palladiumcarbon-hydrogen for reduction of the double bond, cyclization and nitrogroup reduction. The reaction solvent used may be methanol, ethanol,tetrahydrofuran, dimethylformaldehyde or the like, and catalyticreduction may be conducted at ordinary pressure or under pressurization.The reaction time may be from 10 minutes to 30 hours and the reactiontemperature from room temperature to reflux temperature.

<Step E-3>

Isomerization of double bond by light irradiation followed bycyclization. The reaction solvent used may be methanol or the like, withlight irradiation performed in the presence of 2′-acetonaphthone toobtain the target compound (e-4). The reaction time may be from 10minutes to 30 hours.

(wherein the symbols have the same definitions given above.)<Step 2E-1>

Nitration reaction. Compound (2e-1) may be reacted with sulfuric acidand fuming nitric acid to obtain the target compound (2e-2). Thereaction solvent used may be sulfuric acid, fuming nitric acid or thelike, the reaction temperature from 0° C. to room temperature, and thereaction time from 10 minutes to 30 hours.

<Step 2E-2>

Rearrangement of nitro group. Compound (2e-2) may be reacted withsulfuric acid to obtain the target compound (2e-3). The reaction solventused may be sulfuric acid or the like, the reaction temperature from 0°C. to reflux temperature, and the reaction time from 10 minutes to 30hours.

<Step 2E-3>

The target nitro compound (2e-4) may be obtained by nucleophilicsubstitution of compound <2e-3> using any desired nitro group-containingnucleophilic agent and 1-methylpyrrolidone, dimethylformamide,chlorbenzene or the like as the reaction solvent. The reaction may beconducted with addition of an appropriate base, for example, an organicbase such as diisopropylethylamine, or an inorganic base such aspotassium carbonate. The reaction time may be from 10 minutes to 30hours and the reaction temperature from room temperature to refluxtemperature.

<Step 2E-4>

Reduction of nitro group to amino group. The same procedure as in <StepA-5> may be carried out to obtain the target compound (2e-5).

<Step 2E-5>

Condensation of a carboxylic acid and the diamine (2e-5). The diaminecompound (2e-5) may be reacted with a carboxylic acid to obtain thetarget compound (2e-6). The reaction solvent used may be pyrophosphoricacid or the like, the reaction temperature from room temperature toreflux temperature, and the reaction time from 10 minutes to 30 hours.Polyphosphoric acid, phosphorus pentoxide or the like may be used as adehydrating agent.

(wherein the symbols have the same definitions given above.)<Step 3E-1>

This synthesis may be carried out according to the process described inJournal of Heterocyclic Chemistry, 35, 1313 (1998). An α-haloketonederivative (3e-1) may be reacted with malononitrile to synthesizecompound (3e-2). The reaction solvent used may be dimethylformamide orthe like, the reaction temperature from 0° C. to reflux temperature, andthe reaction time from 30 minutes to about 30 hours. Diethylamine may beused as the base.

<Step 3E-2>

Step of forming furopyrimidine ring. Compound (3e-2) may be heated atabout 200° C. in formamide with addition of acetic anhydride to obtainthe target compound (3e-3). The reaction time may be about a few hours.

<Step 3E-3>

Bromination reaction. Compound (3e-3) may be reacted with dibromomethaneand isoamyl nitrite to obtain the target bromo compound (3e-4). Thereaction solvent used may be dibromomethane, the reaction temperaturefrom room temperature to reflux temperature, and the reaction time from30 minutes to 30 hours.

<Step 3E-4>

The same procedure as in <Step A-4> may be carried out to obtaincompound (3e-5).

(wherein the symbols have the same definitions given above.)<Step 3E-5>

The same procedure as in <Step A-1> may be carried out to obtaincompound (3e-7).

<Step 3E-6>

The same procedure as in <Step A-2> may be carried out to obtaincompound (3e-8).

<Step 3E-7>

The same procedure as in <Step A-3> may be carried out to obtaincompound (3e-9).

(wherein the substituent R^(sa100) is optionally substituted phenylaminoor optionally substituted benzyl amino). Synthesis of this compound isdescribed in Journal of Medicinal Chemistry, 40, 3601(1997).

(wherein the substituent R^(sa101) is fluorine, optionally substitutedamino, optionally substituted C₁₋₆ alkoxy or optionally substituted C₂₋₇acylamino). Synthesis of this compound is described in Journal ofMedicinal Chemistry, 39, 1823(1996).[Production Method 7]

Representative production method for compound (II) represented by:

(wherein the symbols have the same definitions given above.) (1)Compound (a-01) represented by the formula:

(wherein the symbols have the same definitions given above) may besynthesized utilizing common hitherto known organic reactions. Ascompound (a-01) there may be used compounds (c-6), (c-10), (2c-4),(d-1), (d-2), (d-7), (3e-4), (2e-4), (3e-9), (4e-1), (4e-2) or (4e-3)described in the aforementioned production methods 4-1, 4-2, 5-1, 5-2and 6.

Compound (II) may be produced using compound (a-01) under the reactionconditions described in <Step A-4> to <Step A-11> in Production Method2-1 above, the reaction conditions described in Production Method 2-2above, the reaction conditions described in Production Method 2-3 aboveand the reaction conditions described in Production Method 3 above.

(wherein the symbols have the same definitions given above.)

The urea derivative (II) may be obtained using compound (a-03) or (a-04)with an appropriate combination of the conditions in <Step A-5> to <StepA-11> in Production Method 2-1. Specifically, compound (a-03) or (a-04)may be, for example, (2c-7), (2c-92), (e-4), (3e-5), (e-3) or (e-6).

[Production Method 8-1]

Representative synthesis method for compound represented by:

(wherein the symbols have the same definitions given above.)

(wherein the symbols have the same definitions given above.)<Step O-1>

Step of reductive amination. An aldehyde derivative may be reductivelyreacted with compound (o-1) to obtain the target compound (o-2). Thereaction solvent used may be acetic acid, tetrahydrofuran,dichloroethane, dichloromethane, methanol or the like, the reactiontemperature from 0° C. to reflux temperature, and the reaction time from30 minutes to 30 hours. The reducing agent used may be sodiumtriacetoxyborohydride, sodium borohydride, or the like.

<Step O-2>

Carbamating step. Compound (o-2) may be reacted with a chloroformatederivative to obtain the target compound (o-3). The reaction solventused may be tetrahydrofuran, dichloromethane or the like, the reactiontemperature from 0° C. to reflux temperature, and the reaction time from30 minutes to 30 hours. Pyridine, triethylamine or the like may be usedas the base.

<Step O-3>

Step of reducing nitro group to amino group. The same procedure as in<Step A-5> may be carried out to obtain compound (o-4).

<Step O-4>

Intramolecular cyclization step. The target compound (o-5) may beobtained by reacting the amino group and carbamate group in themolecule. The reaction solvent used may be tetrahydrofuran,dimethylformamide, dimethylsulfoxide, acetonitrile or the like, thereaction temperature from 0° C. to reflux temperature, and the reactiontime from 30 minutes to 30 hours. Sodium hydride, pyridine,triethylamine or the like may be used as the base.

[Production Method 8-2]

Alternative production method for compound (o-5).

(wherein the symbols have the same definitions given above.)<Step O-5>

Step of reducing nitro group to amino group. The same procedure as in<Step A-5> may be carried out to obtain the target diamine compound(o-6).

<Step O-6>

Intramolecular cyclization step. The target compound (o-5) may beobtained by condensing the two amino groups in the molecule usingphosgene, triphosgene, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride, (1H-1,2,3-benzotriazol-1-yloxy)(tri(dimethylamino))phosphonium hexafluorophosphate,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride,1,1-carbonyldiimidazole or the like as the condensing agent. Thereaction solvent used may be tetrahydrofuran, dimethylformamide,dimethylsulfoxide, acetonitrile or the like, the reaction temperaturefrom 0° C. to reflux temperature, and the reaction time from 30 minutesto 30 hours. Sodium hydride, pyridine, triethylamine or the like may beappropriately used as the base.

[Production Method 9]

Conversion of substituent on ring A of compound (II) represented by

(wherein the symbols have the same definitions given above.)

This may be accomplished by appropriately employing common organicreactions such as oxidation, reduction, esterification, amidation,protection, deprotection, hydrolysis, dehydration, rearrangement,nucleophilic reaction, nucleophilic substitution or aromaticelectrophilic substitution.

Specifically, the substituent conversion on ring A may be carried out bythe methods shown below, for example. In addition, (1) the followingreactions may be appropriately combined, (2) their products may be usedas intermediates as well as final products, and (3) the reactions may beused not only for conversion of substituents directly bonded to ring A,but also for conversion of substituents at positions not directly bondedto but within substituents on ring A.

[Production Method 10]

(wherein G₁ is an optionally substituted nitrogen atom or oxygen atom,and the remaining symbols have the same definitions given above.)<Step H-1>

Reduction of ester compound (h-1) to alcohol compound (h-2). Thereducing agent used may be lithium borohydride, lithium aluminum hydrideor the like, the reaction solvent diethyl ether, tetrahydrofuran or thelike, the reaction temperature from 0° C. to reflux temperature and thereaction time from 10 minutes to 30 hours.

<Step H-2>

Oxidation of alcohol compound (h-2) to aldehyde compound (h-3). Theoxidizing agent used may be manganese dioxide, pyridium chlorochromate(PCC), pyridium dichromate (PDC) or the like, the reaction solventchloroform, dichloromethane, toluene or the like, the reactiontemperature from 0° C. to reflux temperature and the reaction time from30 minutes to 30 hours.

<Step H-3>

Reductive amination reaction. Compound (h-4) may be obtained by reactionof an amino derivative with the aldehyde derivative (h-3) to form animine, followed by reduction with sodium cyanoborohydride or the like.The reaction solvent used may be methanol, tetrahydrofuran or the like,the reaction time from 10 minutes to 30 hours and the reactiontemperature from 0° C. to reflux temperature.

(wherein the symbols have the same definitions given above.)<Step H-4>

Reduction of an ester compound (h-5) to an alcohol compound (h-6). Thesame procedure as in <Step H-1> may be carried out to synthesize thetarget compound (h-6).

<Step H-5>

Oxidation of alcohol compound (h-6) to an aldehyde compound (h-7). Thesame procedure as in <Step H-2> may be carried out to synthesize thetarget compound (h-7).

<Step H-6>

Reductive amination reaction. The same procedure as in <Step H-3> may becarried out to obtain the target compound (h-8) from compound (h-7).

(wherein the symbols have the same definitions given above.)<Step H-7>

Reduction of cyano group to aminomethyl group. The target compound(h-10) may be obtained from compound (h-9) by common catalytic reduction(palladium-carbon, palladium hydroxide-hydrogen or the like). Thereaction solvent used may be tetrahydrofuran, methanol, ethanol or thelike. The reaction time may be from 10 minutes to 30 hours, and thereaction temperature from 0° C. to reflux temperature. Trifluoroaceticacid, hydrochloric acid or the like may be added as an acid.

[Production Method 10-2]

(wherein the symbols have the same definitions given above.)<Step 2H-1>

Step of hydrolyzing ester in compound (2h-1) to obtain compound (2h-2).A base such as potassium hydroxide, sodium hydroxide, calcium carbonate,sodium carbonate or the like may be used for the reaction. The reactiontime may be from 10 minutes to 30 hours, and the reaction temperaturefrom 0° C. to reflux temperature. The solvent used may be water,tetrahydrofuran or the like.

<Step 2H-2>

Synthesis of amide derivative (2h-3) by condensation of carboxylic acidand amine derivative. Compound (2h-3) may be obtained by reactingcompound (2h-2) and an amine derivative in the presence of a condensingagent. As condensing agents there may be used1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride,(1H-1,2,3-benzotriazol-1-yloxy)(tri(dimethylamino))phosphoniumhexafluorophosphate, or the like. The reaction time may be from 10minutes to 30 hours, and the reaction temperature from 0° C. to refluxtemperature. The solvent used may be dimethylformamide, tetrahydrofuran,or the like.

<Step 2H-3>

Synthesis of ester (2h-4) by condensation of carboxylic acid and analcohol. Compound (2h-3) may be obtained by reaction of compound (2h-2)and an alcohol derivative in the presence of a condensing agent. As thecondensing agent there may be used1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, or thelike. The reaction time may be from 10 minutes to 30 hours, and thereaction temperature from 0° C. to reflux temperature. The solvent usedmay be dimethylformamide, tetrahydrofuran, or the like.

(wherein the symbols have the same definitions given above.)<Step 2H-4>

Step of obtaining compound (2h-6) by hydrolysis of ester in compound(2h-5). The same procedure as in <Step 2H-1> may be carried out tosynthesize compound (2h-6) from compound (2h-5).

<Step 2H-5>

Synthesis of amide derivative (2h-7) by condensation of carboxylic acidderivative (2h-6) and amino derivative. The same procedure as in <Step2H-2> may be carried out to synthesize compound (2h-7) from compound(2h-6).

(wherein the symbols have the same definitions given above.)<Step 2H-6>

Step of obtaining nitrile derivative (2h-9) by dehydration of carbamoylcompound (2h-8). The reaction solvent used may be tetrahydrofuran,diethyl ether or the like, the dehydrating agent used may be thionylchloride, trifluoroacetic anhydride, dicyclohexyl carbodiimide or thelike, and the base used may be pyridine, triethylamine or the like. Thereaction temperature may be from 0° C. to reflux temperature, and thereaction time from 30 minutes to 30 hours.

[Production Method 10-3]

(wherein the symbols have the same definitions given above.)<Step 3H-1>

Step of acylating amino group. Compound (3h-1) may be reacted with anacid chloride, acid anhydride or the like to obtain the target compound(3h-2). The reaction solvent used may be tetrahydrofuran or the like,the reaction temperature from 0° C. to reflux temperature, and thereaction time from 10 minutes to 30 hours. Triethylamine or the like maybe used as the base.

(wherein the symbols have the same definitions given above.)<Step 3H-20>

Acylation step. Compound (3h-3) may be reacted with an acid chloride,acid anhydride or the like to obtain the target compound (3h-4). Thereaction solvent used may be tetrahydrofuran, pyridine or the like, thereaction temperature from 0° C. to reflux temperature, and the reactiontime from 10 minutes to 30 hours. Triethylamine, pyridine or the likemay be used as the base.

<Step 3H-21>

Cyclization reaction. The reaction solvent used may be dimethylformamideor the like, the reaction temperature from 100° C. to refluxtemperature, and the reaction time from 10 minutes to 30 hours.Potassium carbonate or the like may be used as the base.

(wherein the symbols have the same definitions given above.)<Step 3H-3>

Sulfonamidation step. Compound (3h-5) may be reacted with a sulfonylchloride derivative to obtain the target compound (3h-6). The reactionsolvent used may be tetrahydrofuran, dimethylformamide or the like, thereaction temperature from 0° C. to reflux temperature, and the reactiontime from 10 minutes to 30 hours. Triethylamine, pyridine or the likemay be used as the base.

(wherein the symbols have the same definitions given above.)<Step 3H-4>

De-benzyloxycarbonylation step. Compound (3h-8) may be obtained fromcompound (3h-7) by ordinary catalytic reduction (palladium-carbon,palladium hydroxide-carbon and hydrogen, etc.). The solvent used may betetrahydrofuran, methanol, ethanol or the like. The reaction time may befrom 10 minutes to 30 hours and the reaction temperature from 0° C. toreflux temperature. Trifluoroacetic acid, hydrochloric acid or the likemay be added as an acid.

[Production Method 11]

(wherein the symbols have the same definitions given above.)<Step I-1>

Rearrangement of carboxylic acid to amino derivative (i-2). A carboxylicacid derivative (i-1) may be reacted with benzyl alcohol in the presenceof diphenylphosphoryl azide and triethylamine to obtain compound (i-2)from compound (i-1). The reaction solvent used may be benzyl alcohol,dimethylformamide, toluene or the like, the reaction temperature fromroom temperature to reflux temperature, and the reaction time from 10minutes to 30 hours.

<Step I-2>

The same procedure as in <Step A-4>, <Step A-5> and <Step A-7> may becarried out to synthesize compound (i-3) from compound (i-2).

(wherein the symbols have the same definitions given above.)<Step I-3>

Step of rearrangement of carbamoyl group to amino group.

An amino compound (i-5) may be obtained from compound (i-4) by reactionwith a base such as bromine water, sodium hydroxide or the like. Thereaction solvent used may be water or the like, the reaction temperaturefrom room temperature to reflux temperature, and the reaction time from10 minutes to 10 hours.

[Production Method 12-1]

(wherein the symbols have the same definitions given above.)<Step M-1>

Conversion of methylthio group to methylsulfone group.

Compound (m-1) may be reacted with a peracid to obtain the targetcompound (m-2). The peracid used may be 3-chloroperbenzoic acid, thereaction solvent methylene chloride, chloroform or the like, thereaction time from 10 minutes to 30 hours and the reaction temperaturefrom 0° C. to room temperature.

[Production Method 12-2]

(wherein the symbols have the same definitions given above.)<Step 2M-1>

Step of introducing substituent into aromatic ring by electrophilicreaction. An electrophilic reagent may be reacted with compound (2m-1)to obtain compound (2m-2) The electrophilic reagent used for thereaction may be, as specific examples, Vilsmeier reagent (which may beprepared from dimethylformamide or N-methylformanilide and phosphorusoxychloride), N-chlorosuccinimide, N-bromosuccinimide, a combination ofacyl chloride and a Lewis acid (for example, aluminum chloride, titaniumtetrachloride, etc.) or a reagent represented by the formula

These allow introduction of formyl, chloro, bromo, acyl anddimethylaminomethyl groups, respectively. The reaction solvent used maybe dimethylformamide, acetonitrile, dichloromethane, toluene or thelike. The reaction temperature maybe from 0° C. to reflux temperature,and the reaction time from 10 minutes to 30 hours.[Production Method 13]

(wherein the symbols have the same definitions given above.)<Step Q-1>

Step of deprotection of hydroxyl-protecting group of compound (q-1). Thereaction may be conducted in the same manner as the conventional methodfor deprotection of a phenol group protected with a benzyl group.Specifically, the reagent used may be, for example, trifluoroaceticacid-thioanisole, palladium hydroxide-hydrogen, platinum oxide-hydrogen,or the like. The reaction solvent used may be trifluoroacetic acid,dimethylformamide or the like, the reaction time from 10 minutes to 30hours and the reaction temperature from room temperature to refluxtemperature.

(wherein R^(sa90) is an amino or nitro group, and the other symbols havethe same definitions given above.)<Step Q-2>

Step of deprotection of hydroxyl-protecting group of compound (q-3). Thereaction may be conducted under the same conditions as in <Step Q-1>above.

[Production Method 14]

(wherein the symbols have the same definitions given above.)<Step R-1>

Step of reacting compound (r-1) with an electrophilic reagent such as analkyl halide derivative (r-2) to obtain compound (r-3). The reactionsolvent used may be dimethylformamide, dimethylsulfoxide,tetrahydrofuran or the like, the reaction time from 10 minutes to 30hours, and the reaction temperature from 0° C. to reflux temperature.The reaction may also employ a base, and specifically, for example,potassium carbonate, cesium carbonate or the like.

As specific examples for the alkyl halide derivative (R^(sa71)—U) in thereaction there may be mentioned (1) alkylthio halide derivativesrepresented by the formula: R^(sa80)S—(CH₂)_(s)—Cl (wherein s is aninteger of 1-6, and the other symbols have the same definitions givenabove), (2) alkyl halide derivatives represented by the formula:Br—(CH₂)_(s)—Cl (wherein s is an integer of 1-6), (3) propylene oxidederivatives represented by the formula:

(wherein U is a leaving group), (4) compounds represented by theformula:

(wherein U is a leaving group, R^(sa82) is an amino-protecting groupsuch as t-butoxycarbonyl or benzyl, and s is an integer of 1-6), and (5)alkyl halide derivatives substituted with C₁₋₆ alkoxy groups.

(wherein R^(sa73) is hydrogen or 2-(trimethylsilyl)ethoxymethyl, and theother symbols have the same definitions given above.<Step R-2>

Step of reaction with a phenol derivative (r-4) to introduce thesubstituent R^(sa71). The substituent R^(sa71) may be introduced by thesame procedure as in <Step R-1>.

(wherein the symbols have the same definitions given above.)<Step R-3>

Step of triflating the hydroxyl group. Compound (r-6) may be reactedwith a triflating reagent such as paranitrophenyl triflate or the liketo obtain the target compound (r-7). The reaction solvent used may bedimethylformamide or the like, the reaction temperature from 0° C. toreflux temperature and the reaction time from 10 minutes to 30 hours.Potassium carbonate or the like may be used as a base.

<Step R-4>

Step of converting the triflate group to a cyano group. Compound (r-7)may be reacted with a cyanating reagent such as zinc cyanide (Zn(CN)₂)or the like to obtain the target compound (r-8). The catalyst used maybe tetrakistriphenylphosphine palladium. The reaction solvent used maybe dimethylformamide, the reaction temperature from room temperature toreflux temperature, and the reaction time from 10 minutes to 30 hours.

(wherein the symbols have the same definitions given above.)<Step R-5>

Step of reacting compound (r-3) which has a thioether group insubstituent R^(sa71), with an oxidizing agent such as 3-chloroperbenzoicacid to obtain compound (2r-2). The reaction solvent used may bemethylene chloride, chloroform or the like, the reaction time from 10minutes to 30 hours and the reaction temperature from 0° C. to roomtemperature.

<Step R-6>

Step of reacting a nucleophilic agent with compound (r-3) having aleaving group, for example, a halogen atom such as chlorine, bromine oriodine or a methanesulfonyloxy group, or an epoxide group or the like insubstituent R^(sa71), to obtain compound (2r-1) or compound (2r-4).Specific examples of nucleophilic agents which may be used includenitrogen-containing aromatic derivatives such as triazole or imidazole,amine derivatives such as morpholine or pyrrolidine, and alcoholderivatives, phenol derivatives, thiol derivatives and the like.

The reaction solvent used may be dimethylformamide, tetrahydrofuran, orthe like, the reaction time from 10 minutes to 30 hours and the reactiontemperature from 0° C. to reflux temperature, and potassium carbonate,sodium hydride or the like may be used as a base.

<Step R-7>

(wherein R^(sa82) is an amino-protecting group such as t-butoxycarbonylor benzyl, and the remaining symbols have the same definitions givenabove.)

Compound (r-90) or compound (r-91) wherein the amino group protectedwith a protecting group may be subjected to amino-deprotection reaction,and the deprotected amino group then alkylated.

(1) Amino-deprotecting step. The deprotecting reagent used may betrifluoroacetic acid, hydrochloric acid or the like. When the protectinggroup is benzyl, the deprotecting reaction may be conducted by commoncatalytic reduction (palladium hydroxide-hydrogen or the like). Thesolvent used may be trifluoroacetic acid, methanol, ethanol or the like.The reaction time may be from 10 minutes to 30 hours and the reactiontemperature from 0° C. to reflux temperature.

(2) Step of alkylating deprotected amino group. The deprotected aminoderivative may be reacted with an aldehyde derivative or ketonederivative to form an imine, which is then reduced with a reducing agentsuch as sodium cyanoborohydride to obtain compound (2r-3). The reactionsolvent used may be methanol, tetrahydrofuran or the like, the reactiontime from 10 minutes to 30 hours, and the reaction temperature from 0°C. to reflux temperature.

[Production Method 15]

Alternative synthesis method for compound represented by:

(wherein the symbols have the same definitions given above.)

(wherein the symbols have the same definitions given above.)<Step P-1>

Compound (p-1) may be reacted with an alcohol derivative (p-2) in thepresence of a base such as sodium hydride to obtain compound (p-3). Thesynthesis may be carried out by reaction in a solvent such as1-methylpyrrolidone or N,N-dimethylformamide. The reaction time may befrom 10 minutes to 30 hours, and the reaction temperature from 0° C. toreflux temperature.

[Production Method 16]

Alternative synthesis method for compound represented by:

(wherein the symbols have the same definitions given above.)

(wherein the symbols have the same definitions given above.)<Step P-2>

Reaction for obtaining carbamate derivative. It may be obtained byreacting an amino derivative with phenyl chloroformate. The reactionsolvent used may be tetrahydrofuran, dimethylformamide or the like, thereaction temperature from 0° C. to reflux temperature, and the reactiontime from 30 minutes to 30 hours.

The reaction is carried out while appropriately protecting the reactivefunctional groups such as amino, hydroxyl and carboxyl.

As amino-protecting groups there may be used any groups conventionallyknown as protecting groups for amino groups in organic synthesis, withno particular restrictions, and as specific examples there may bementioned substituted or unsubstituted lower alkanoyl groups such asformyl, acetyl, chloroacetyl, dichloroacetyl, propionyl, phenylacetyl,phenoxyacetyl and thienylacetyl; substituted or unsubstituted loweralkoxycarbonyl groups such as benzyloxycarbonyl, t-butoxycarbonyl andp-nitrobenzyloxycarbonyl; substituted lower alkyl groups such as methyl,t-butyl, 2,2,2-trichloroethyl, trityl, p-methoxybenzyl, p-nitrobenzyl,diphenylmethyl and pivaloyloxymethyl; substituted silyl groups such astrimethylsilyl and t-butyldimethylsilyl; substituted silylalkoxyalkylgroups such as trimethylsilylmethoxymethyl, trimethylsilylethoxymethyl,t-butyldimethylsilylmethoxymethyl and t-butyldimethylsilylethoxymethyl;or substituted or unsubstituted benzylidene groups such as benzylidene,salicylidene, p-nitrobenzylidene, m-chlorbenzylidene,3,5-di(t-butyl)-4-hydroxybenzylidene and 3,5-di(t-butyl)benzylidene.

These protecting groups may be removed by ordinary methods such ashydrolysis or reduction, depending on the type of protecting group used.

As hydroxyl-protecting groups there may be used any groupsconventionally known as protecting groups for hydroxyl groups in organicsynthesis, with no particular restrictions, and as specific examplesthere may be mentioned lower alkylsilyl groups such as trimethylsilyland t-butyldimethylsilyl; lower alkoxymethyl groups such asmethoxymethyl and 2-methoxyethoxymethyl; tetrahydropyranyl; aralkylgroups such as benzyl, p-methoxybenzyl, 2,4-dimethoxybenzyl,o-nitrobenzyl, p-nitrobenzyl and trityl; acyl groups such as formyl andacetyl; lower alkoxycarbonyl groups such as t-butoxycarbonyl,2-iodoethoxycarbonyl and 2,2,2-trichloroethoxycarbonyl;alkenyloxycarbonyl groups such as 2-propenyloxycarbonyl,2-chloro-2-propenyloxycarbonyl, 3-methoxycarbonyl-2-propenyloxycarbonyl,2-methyl-2-propenyloxycarbonyl, 2-butenyloxycarbonyl andcinnamyloxycarbonyl; and aralkyloxycarbonyl groups such asp-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl andp-nitrobenzyloxycarbonyl.

These protecting groups may be removed by ordinary methods such ashydrolysis or reduction, depending on the type of protecting group used.

As carboxyl-protecting groups there may be used any groupsconventionally known as protecting groups for carboxyl groups in organicsynthesis, with no particular restrictions, and as specific examplesthere may be mentioned linear or branched lower alkyl groups of 1-4carbons such as methyl, ethyl, isopropyl and t-butyl; halogeno loweralkyl groups such as 2-iodoethyl and 2,2,2-trichloroethyl; loweralkoxymethyl groups such as methoxymethyl, ethoxymethyl andisobutoxymethyl; lower aliphatic acyloxymethyl groups such asbutyryloxymethyl and pivaloyloxymethyl; 1-lower alkoxycarbonyloxyethylgroups such as 1-methoxycarbonyloxyethyl and 1-ethoxycarbonyloxyethyl,aralkyl groups such as benzyl, p-methoxybenzyl, o-nitrobenzyl andp-nitrobenzyl; benzhydryl, phthalidyl, and the like.

These protecting groups may be removed by ordinary methods such ashydrolysis or reduction, depending on the type of protecting group used.

There are no particular restrictions on esters of the carboxyl groups solong as they are ones commonly used in organic synthesis, and theyinclude physiologically acceptable esters which are hydrolyzed underphysiological conditions. As specific examples there may be mentionedalkyl groups of 1 to 6 carbons, aryl groups of 6 to 12 carbons, aralkylgroups of 7 to 20 carbons such as benzyl, heteroarylalkyl groups of 7 to20 carbons, 4-methoxybenzyl, alkanoyloxyalkyl groups such asacetoxymethyl, propionyloxymethyl or pivaloxymethyl,alkoxycarbonyloxyalkyl groups such as methoxycarbonyloxymethylethoxycarbonyloxymethyl or 2-methoxycarbonyloxyethyl,(5-methyl-2-oxo-1,3-dioxo-4-yl)-methyl, and the like.

The solvents to be used for the invention are not particularlyrestricted so long as they do not impede the reaction and are solventscommonly used in organic synthesis, and as examples there may bementioned lower alcohols such as methanol, ethanol, propanol andbutanol, polyalcohols such as ethyleneglycol and glycerin, ketones suchas acetone, methylethyl ketone, diethyl ketone and cyclohexanone, etherssuch as diethyl ether, isopropyl ether, tetrahydrofuran, dioxane,2-methoxyethanol and 1,2-dimethoxyethane, nitriles such as acetonitrileand propionitrile, esters such as methyl acetate, ethyl acetate,isopropyl acetate, butyl acetate and diethyl phthalate, halogenatedhydrocarbons such as dichloromethane, chloroform, carbon tetrachloride,1,2-dichloroethane, trichloroethylene and tetrachloroethylene, aromaticcompounds such as benzene, toluene, xylene, monochlorbenzene,nitrobenzene, indene, pyridine, quinoline, collidine and phenol,hydrocarbons such as pentane, cyclohexane, hexane, heptane, octane,isooctane, petroleum benzine and petroleum ether, amines such asethanolamine, diethylamine, triethylamine, pyrrolidine, piperidine,piperazine, morpholine, aniline, dimethylaniline, benzylamine andtoluidine, amides such as formamide, N-methylpyrrolidone,N,N-dimethylimidazolone, N,N-dimethylacetamide andN,N-dimethylformamide, phosphoric/phosphorous amides such ashexamethylphosphosphoric triamide and hexamethylphosphoroustriamide, andwater, as well as other commonly used solvents, either alone or inmixtures of two or more, with no particular restrictions on the solventratio.

There are no particular restrictions on bases uses so long as they arecommonly known as bases for organic synthesis, and as specific examplesthere may be mentioned sodium carbonate, sodium bicarbonate, potassiumcarbonate, sodium hydride, potassium hydride, t-butoxypotassium,pyridine, dimethylaminopyridine, trimethylamine, triethylamine,N,N-diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine,N-methylpiperidine, N,N-dimethylaniline,1,8-diazabicyclo[5,4,0]undeca-7-ene (DBU), pyridine,4-dimethylaminopyridine, picoline, lutidine, quinoline, isoquinoline,sodium hydroxide, potassium hydroxide, lithium hydroxide, butyllithium,and sodium or potassium alcoholates such as sodium methylate, potassiummethylate and sodium ethylate.

As specific examples of halogenating agents to be used there may bementioned halogenating agents conventionally used for synthesis of acidhalides, for example, phosgene, diphosgene (phosgene dimer), triphosgene(phosgene trimer), thionyl chloride, thionyl bromide, phosphorustrichloride, phosphorus tribromide, phosphorus oxychloride, phosphoruspentachloride, trichloromethyl chloroformate and oxalyl chloride, aswell as Vilsmeier reagents obtained by reacting these halogenatingagents with acid amides or phosphoric amides.

There are no particular restrictions on reducing agents so long as theyare ones commonly used in organic synthesis, and as examples there maybe mentioned contact hydrogenating catalysts such as NaBH₄, LiBH₄,Zn(BH₄)₂, Me₄NBH(OAc)₃, NaBH₃CN, Selectride, Super Hydride (LiBHEt₃),LiAlH₄, DIBAL, LiAlH (t-BuO)₃, Red-al and binap, as well as platinum,palladium, rhodium, ruthenium, nickel, and the like.

After completion of the reaction, purification may be accomplished byany desired ordinary treatment method, such as column chromatographyusing silica gel or an adsorption resin, or recrystallization from asuitable solvent.

Throughout the present specification, the term “pharmacologicallyacceptable salt” is not particularly restrictive on the type of salt,and as examples of such salts there may be mentioned inorganic acidaddition salts such as hydrochloric acid salts, sulfuric acid salts,carbonic acid salts, bicarnobate salts, hydrobromic acid salts andhydriodic acid salts; organic carboxylic acid addition salts such asacetic acid salts, maleic acid salts, lactic acid salts, tartaric acidsalts and trifluoroacetic acid salts; organic sulfonic acid additionsalts such as methanesulfonic acid salts, hydroxymethanesulfonic acidsalts, hydroxyethanesulfonic acid salts, benzenesulfonic acid salts,toluenesulfonic acid salts and taurine salts; amine addition salts suchas trimethylamine salts, triethylamine salts, pyridine salts, procainesalts, picoline salts, dicyclohexylamine salts,N,N′-dibenzylethylenediamine salts, N-methylglucamine salts,diethanolamine salts, triethanolamine salts,tris(hydroxymethylamino)methane salts and phenethylbenzylamine salts;and amino acid addition salts such as arginine salts, lysine salts,serine salts, glycine salts, aspartic acid salts and glutamic acidsalts.

The dosage of a medicine according to the invention will differdepending on the severity of symptoms, patient age, gender and weight,administration form and type of disease, but administration may usuallybe from 100 μg to 10 g per day for adults, either at once or in divideddoses.

There are no particular restrictions on the form of administration of amedicine according to the invention, and it may usually be administeredorally or parenterally by conventional methods.

Common excipients, binders, glossy agents, coloring agents, tastecorrectors and the like, and if necessary stabilizers, emulsifiers,absorption promoters, surfactants and the like, may also be used forformulation, with inclusion of components ordinarily used as startingmaterials for formulation of pharmaceutical preparations by commonmethods.

Examples of such components which may be used include animal andvegetable oils (soybean oil, beef tallow, synthetic glycerides, etc.),hydrocarbons (liquid paraffin, squalane, solid paraffin, etc.), esteroils (octyldodecyl myristate, isopropyl myristate, etc.), higheralcohols (cetostearyl alcohol, behenyl alcohol, etc.), silicone resins,silicone oils, surfactants (polyoxyethylene fatty acid esters, sorbitanfatty acid esters, glycerin fatty acid esters, polyoxyethylenesorbitanfatty acid esters, polyoxyethylene hydrogenated castor oil,polyoxyethylenepolyoxypropylene block copolymer, etc.), water-solublepolymers (hydroxyethyl cellulose, polyacrylic acid, carboxyvinylpolymer, polyethyleneglycol, polyvinylpyrrolidone, methyl cellulose,etc.), alcohols (ethanol, isopropanol, etc.), polyhydric alcohols(glycerin, propyleneglycol, dipropyleneglycol, sorbitol, etc.), sugars(glucose, sucrose, etc.), inorganic powders anhydride, aluminiummagnesium silicate, aluminium silicate, etc.), purified water and thelike. For pH adjustment there may be used inorganic acids (hydrochloricacid, phosphoric acid, etc.), alkali metal salts of inorganic acids(sodium phosphate, etc.), inorganic bases (sodium hydroxide, etc.),organic acids (lower fatty acids, citric acid, lactic acid, etc.),alkali metal salts of organic acids (sodium citrate, sodium lactate,etc.), and organic bases (arginine, ethanolamine, etc.). If necessary,preservatives, antioxidants and the like may also be added.

The compounds of the invention exhibit powerful in vitro inhibitionof 1) invasive tube formation by vascular endothelial cells induced by acombination of angiogenic factors, 2) tube formation by vascularendothelial cells specifically induced by single angiogenic factors, and3) receptor kinases for various angiogenic factors. Among these compoundgroups having such activity there were also found compounds that inhibitproliferation of cancer cells. Invasion and tube formation byendothelial cells are an important process in angiogenesis, andtherefore compounds with inhibiting action against them exhibitangiogenesis-inhibiting effects. In addition, angiogenesis in the bodyis known to depend not on a single angiogenic factor but rather on theadditive and synergistic effect of multiple angiogenic factors ((1)Koolwijk P, van Erck M G M, de Vree W J A, Vermeer M A, Weich H A, Hanemaaijer R, van Hinsbergh V W M. Cooperative effect of TNF-alpha, bFGFand VEGF on the formation of tubular structures of human microvascularendothelial cells in a fibrin matrix. Role of urokinase activity. J.Cell Biol. 1996, 132, P1177-1188.; (2) Tallquist M D, Soriano P,Klinghoffer R A. Growth factor signaling pathways in vasculardevelopment. Oncogene 1999, 18, P7917-7932.). Thus, the compounds of theinvention which inhibit tube formation induced by multiple angiogenicfactors produced by cancer cells and the like are expected to exhibitpowerful angiogenesis inhibition in vivo, and should be highly useful asangiogenesis inhibitors.

The biochemical activity of the compounds of the invention and theirfunction and effect as medicines (angiogenesis-inhibiting activity,antitumor activity, etc.) may be evaluated by the methods describedbelow.

The following is a list of abbreviations used in the pharmacologicaltest examples described below.

LIST OF ABBEVIATIONS

-   DNA: Deoxyribonucleic Acid-   VEGFR2: Vascular Endothelial Growth Factor Receptor 2-   Hepes: N-[2-Hydroxyethyl]piperazine-N′-[2-ethanesulfonic acid]-   MgCl₂: Magnesium chloride-   MnCl₂: Manganese chloride-   Na₃VO₄: Sodium Orthovanadate (V)-   ATP: Adenosine 5′-Triphosphate-   EDTA: Ethylenediaminetetraacetic acid-   HTRF: Homogenous Time-Resolved Fluorescence-   FGFR1: Fibroblast Growth Factor Receptor 1-   PDGFRβ: Platelet-Derived Growth Factor Receptor β-   HGFR: Hepatocyte Growth Factor Receptor-   EGFR: Epidermal Growth Factor Receptor-   Tris: Tris(hydroxymethyl)aminomethane-   NaCl: Sodium chloride-   BSA: Bovine Serum Albumin-   HRP: Horseradish peroxidase-   EGTA: Ethylene glycol bis(2-aminoethyl ether)-N,N,N′,N′-tetraacetic    acid-   SDS: Sodium Dodecyl Sulfate-   NP-40: Nonidet P-40-   PCR: Polymerase Chain Reaction-   RT-PCR: Reverse Transcription-Polymerase Chain Reaction-   RNA: Ribonucleic Acid-   cDNA: complementary DNA-   cRNA: complementary RNA-   dNTP: dATP, dCTP, dGTP, dTTP-   UTP: Uridine 5′-Triphosphate-   CTP: Cytidine 5′-Triphosphate-   dATP: 2′-Deoxyadenosine 5′-Triphosphate-   dCTP: 2′-Deoxycytidine 5′-Triphosphate-   dGTP: 2′-Deoxyguanosine 5′-Triphosphate-   dUTP: 2′-Deoxyuridine 5′-Triphosphate-   GAPDH: Glyceraldehyde 3-Phosphate Dehydrogenease-   FBS: Fetal Bovine Serum-   PBS: Phosphate Buffered Saline-   MIT: (3-[4,5-Dimethlythiazol-2-yl]-2,5-diphenyltetrazolium bromide;    Thiazolyl blue-   DMSO: Dimethyl Sulfoxide-   PDGF: Platelet-Derived Growth Factor-   EGF: Epidermal Growth Factor-   FGF2: Fibroblast Growth Factor 2-   VEGF: Vascular Endothelial Growth Factor-   HGF: Hepatocyte Growth Factor-   TNF-α: Tumor Necrosis Factor alpha-   FCS: Fetal Calf Serum-   EGM-2: Endothelial cell Growth Medium-2

Pharmacological Test Example 1 Inhibition Against Invasive TubeFormation by Vascular Endothelial Cells in Response to Stimulation byAngiogenic Factor Mixture

Human Umbilical Vein Endothelial Cells (HUVECs) were isolated accordingto a reported method (Shinseikagaku Jikken Koza [New BiochemistryExperiment Lectures], “Saibo Baiyo Gijutsu” [Cell Culturing Techniques],p. 197-202), and were cultured in a 5% CO₂ incubator (37° C.) usingEGM-2 medium (purchased from Clonetics Corp.) until the cells reachedconfluency. After adding 0.4 ml of bovine fibrinogen (purchased fromSigma Co.) to the inner well of a Transwell culturing plate (purchasedfrom Coster Inc.), it was hardened with 0.7 units/ml of thrombin(purchased from Sigma Co.). The HUVECs were recovered using trypsin-EDTAand then suspended in human endothelial serum free mediumbasal growthmedium (hereinafter abbreviated as SFM, purchased from GIBCO BRL), and0.4 ml of the cell suspension (1.4×10⁵ cells) was seeded onto thehardened fibrin gel and cultured for approximately 4 hours in a 5% CO₂incubator (37° C.). After 4 hours, there was added to the outer chamberof the Transwell 1.5 ml of an SFM solution containing a mixture ofangiogenic factors {10 ng/ml EGF (purchased from GIBCO BRL), 30 ng/mlFGF2 (purchased from GIBCO BRL), 75 ng/ml VEGF (purchased from Wako PureChemical Industries Co., Ltd.), 50 ng/ml HGF (purchased from R&D Co.)and 7.5 ng/ml TNF-α (purchased from Genzyme Corp.) [The concentrationsof the angiogenic factors differed slightly according to the HUVEClot.]} and a diluted test substance, and culturing was carried out in a5% CO₂ incubator (37° C.). On the 2nd and 4th days after adding the testsubstance, the medium was exchanged with 1.5 ml of freshly prepared SFMsolution containing the angiogenic factor mixture and test substance.Upon aspirating off the culture supernatant in the inner well on the 6thday after the initial addition of the test substance, 0.4 ml of a 3.3mg/ml MTT solution dissolved in PBS (purchased from Sigma Corp.) wasadded and culturing was performed for approximately 1 hour in a 5% CO₂incubator (37° C.). The number of tubes formed in the fibrin gel stainedwith MTT was scored based on microscope observation. Specifically, thenumber of tubes formed in the absence of the test substance wasdesignated as +++, while − was assigned if absolutely no tubes formed.The number of tubes formed in the presence of the test substance wasscored on the 5-level scale of +++, ++, +, +/−, − to evaluate thestrength of inhibition of the test substance.

TABLE 1 [Pharmacological Test Example 1: Inhibition against invasivetube formation by vascular endothelial cells in response to stimulationby angiogenic factor mixture] Example No. 0.01 μM 0.1 μM 1.0 μM 25 +++/− +/− 53 +++ +/− − 55 +++ +/− +/− 72 +++ − − 74 ++ − − 75 +++ +/− − 81++ − − 100 ++ +/− +/− 153 +/− − − 172 + +/− +/− 189 +/− − − 212 +/− − −245 +/− − − 298 +/− − − 316 +/− − − 348 +/− − − 368 − − − 374 +/− − −404 − − − 415 +/− − − 422 + − −

Pharmacological Test Example 2 Inhibition Against Sandwich tubeFormation by Vascular Endothelial Cells in Response to Stimulation byAngiogenic Factor

Human Umbilical Vein Endothelial Cells (HUVECs) were isolated by thesame method as in Pharmacological Test Example 1, and were cultured in a5% CO₂ incubator (37° C.) using EGM-2 medium (purchased from CloneticsCorp.) until the cells reached confluency.

An ice-cooled mixture of collagen:5×RPMI 1640:reconstitution buffer (allpurchased from Nitta Gelatin, Inc.) at 7:2:1 was dispensed at 0.4 mlinto each well of a 24-well plate, and then stationed for 40 minutes ina 5% CO₂ incubator (37° C.) for gelling. The HUVECs were recovered usingtrypsin-EDTA and then suspended in human endothelial serum free medium(SFM, purchased from GIBCO BRL) containing added angiogenic factors [20ng/ml FGF2 (purchased from GIBCO BRL) and 10 ng/ml EGF (purchased fromGIBCO BRL), or 25 ng/ml VEGF (purchased from Wako Pure ChemicalIndustries Co., Ltd.) and 10 ng/ml EGF, or 30 ng/ml HGF (purchased fromR&D Co.) and 10 ng/ml EGF], and the cell suspension was added at 0.4 mlto each well (with the cell counts differing slightly according to theHUVEC lot), and cultured overnight in a 5% CO₂ incubator (37° C.). Onthe following day, the medium on the upper layer was aspirated off, andthen 0.4 ml of an ice-cooled mixture of collagen:5×RPMI1640:reconstitution buffer (all purchased from Nitta Gelatin, Inc.) at7:2:1 was superposed into each well prior to stationing for 4 hours in a5% CO₂ incubator (37° C.) for gelling. After adding 1.5 ml of an SFMsolution containing each of the aforementioned angiogenic factors and adiluted test substance onto the upper layer, culturing was performed ina 5% CO₂ incubator (37° C.). Upon aspirating off the culture supernatantin each well on the 4th day after addition of the test substance, 0.4 mlof a 3.3 mg/ml MTT solution dissolved in PBS (purchased from SigmaCorp.) was added to each well and culturing was performed forapproximately 2 hours in a 5% CO₂ incubator (37° C.). The tubes formedin the collagen gel of each well were stained by the MTT, the tubeimages were loaded into a computer (Macintosh), and the total length ofthe tubes was determined by image analysis software “MacScope”(purchased from Mitani Corp.). The ratio of the total length of thetubes formed in the well containing the test substance with respect tothe total length of the tubes formed in the well containing no testsubstance was expressed as a percentage, and the concentration of eachtest substance required for 50% inhibition of tube formation (IC₅₀) wasdetermined from the ratio value.

TABLE 2 [Pharmacological Test Example 2: Inhibition against sandwichtube formation by vascular endothelial cells in response to stimulationby VEGF] Example No. IC₅₀ (nM) Example No. IC₅₀ (nM) 1 310 12 44 19 2823 100 53 9.9 55 35 59 170 65 5.9 70 58 72 22 74 5.9 75 1.4 81 1.8 1006.3 108 4.9 116 8.1 121 42 127 7.5 129 40 137 10 153 0.02 155 1.4 1570.9 159 0.6 186 23 189 0.3 198 1.5 202 15 204 0.9 211 0.3 215 22 224 26249 1.6 253 40 256 36 265 0.6 266 0.6 283 36 289 4.6 296 34 298 0.7 2991.0 300 7.5 304 0.3 308 5.2 314 4.2 316 1.0 320 2.5 325 1.0 326 1.0 32756 346 25 368 5.4 372 44 374 3.0 381 4.7 382 4.6 386 10 404 2.8 405 28408 39 415 3.8 419 10 422 4.8 433 5.6 436 22 440 1.4 441 3.6 442 7.2 4445.5 445 6.2 446 4.0 450 4.5 454 3.7 455 7.8 463 26 490 26 492 7.2 4939.0 494 9.3 497 4.6 503 6.4 504 4.6 505 8.9 518 1.3 520 1.5 521 0.5 57813

Pharmacological Test Example 3 Measurement of Inhibition AgainstReceptor Tyrosine Kinase Activity

This assay is used to determine inhibition of a test substance ontyrosine kinase activity. DNA coding for the cytoplasmic domain ofVEGFR2 is obtained by total cDNA synthesis (Edwards M, InternationalBiotechnology Lab 5(3), 19-25, 1987) or by cloning. Expression in anappropriate expression system can produce a polypeptide with tyrosinekinase activity. The cytoplasmic domain of VEGFR2 obtained by expressionof recombinant protein in, for example, insect cells has been found toexhibit intrinsic tyrosine kinase activity. For VEGFR2 (GenbankAccession No. L04947), the 1.7 kb DNA fragment described by Terman etal. (Oncogene, 6(9), 1677-1683, 1991), coding for the cytoplasmicdomain, beginning with lysine 791 and including the termination codon,was isolated from a human placental cDNA library (purchased fromClontech Laboratories, Inc.) and cloned in a Baculovirus expressionvector (pFastBacHis, purchased from GIBCO BRL). The recombinantconstruct was transfected into insect cells (Spondoptea frugiperda9(Sf9)) to prepare a recombinant Baculovirus. (Instructions forpreparation and use of recombinant Baculovirus may be found in standardtexts, such as “Bac-To-Bac Baculovirus Expression System” (GIBCO BRL).)The cytoplasmic fragment starting from lysine 398 (FGFR1, GenbankAccession No. X52833), the cytoplasmic fragment starting from lysine 558(PDGFRβ, Genbank Accession No. M21616) or the cytoplasmic fragmentstarting from lysine 974 (HGFR, Genbank Accession No. J02958) may becloned and expressed by the same method for use in assays for othertyrosine kinases. EGFR was purchased from Sigma Co. (Product No.E-2645).

For expression of the VEGFR2 tyrosine kinase, Sf9 cells were infectedwith the VEGFR2 recombinant virus and collected after 48 hours. Thecollected cells were rinsed with ice-cooled phosphate buffered saline(PBS) and then resuspended using 20 ml of ice-cooled Lysis Buffer (50 mMTris-HCl (pH 8.5), 5 mM 2-mercaptoethanol, 100 mM KCl, 1 mMphenylmethylsulfonyl fluoride, 1% (v/v) NP-40) per 1.5×10⁸ cells. Thesuspension was centrifuged at 12,000 rpm for 30 minutes at 4° C. and thesupernatant was obtained.

The supernatant was added to a Ni-NTA agarose column (3 ml, purchasedfrom Qiagen) equilibrated with Buffer A {20 mM Tris-HCl (pH 8.5), 5 mM2-mercaptoethanol, 500 mM KCl, 20 mM imidazole, 10% (v/v) glycerol}. Thecolumn was washed with 30 ml of Buffer A, and then with 6 ml of Buffer B{20 mM Tris-HCl (pH 8.5), 5 mM 2-mercaptoethanol, 1M KCl, 10% (v/v)glycerol}, and finally with 6 ml of Buffer A. After washing, it waseluted with 6 ml of Buffer C {20 mM Tris-HCl (pH 8.5), 5 mM2-mercaptoethanol, 100 mM KCl, 100 mM imidazole, 10% (v/v) glycerol}.The eluate was placed on a dialysis membrane (purchased from SpectrumLaboratories) and dialyzed with a dialysis buffer {20 mM Tris-HCl (pH7.5), 10% (v/v) glycerol, 1 mM dithiothreitol, 0.1 mMNa₃VO₄, 0.1 mMEGTA}. After dialysis, it was supplied for SDS-electrophoresis, and therecombinant protein (His6-VEGFR2, cytoplasmic domain of VEGFR2 fusedwith 6 histidine residues at the N-terminus) detected at a molecularweight of approximately 100 kDa with Coumassie Brilliant Blue stainingwas assayed using BSA (bovine serum albumin, purchased from Sigma Co.)as the standard substance, and stored at −80° C. until use. Using thesame method for the cytoplasmic domains of FGFR1, PDGFRβ and HGFRyielded respective recombinant proteins fused with 6 histidine residuesat the N-termini (His6-FGFR1, His6-PDGFRβ or His6-HGFR).

The tyrosine kinase reaction was conducted as follows. In the case ofVEGFR2, for example, 10 μl of a kinase reaction solution {200 mM Hepes(pH 7.4), 80 mM MgCl₂, 16 mM MnCl₂, 2 mM Na₃VO₄}, 250 ng of biotin-boundpoly(Glu4:Tyr1) (biotin-poly(GT), purchased from CIS Diagnostics Co.) (6μl of a 15-fold dilution with distilled water), 15 ng of His6-VEGFR2 (10μl of a 240-fold dilution with 0.4% BSA solution) and the test substancedissolved in dimethylsulfoxide (4 μl of a 100-fold dilution with 0.1%BSA solution) were added into each well of a 96-well round-bottom plate(NUNC Co., Product No. 163320), to a total of 30 μl. Next, 10 μl of 4 μMATP (diluted with distilled water) was added prior to incubation at 30°C. for 10 minutes, and then 10 μl of 500 mM EDTA (pH 8.0) was added.

The tyrosine phosphorylated biotin-poly(GT) was measured by theHomogenous Time-Resolved Fluorescence (HTRF) method (AnalyticalBiochemistry, 269, 94-104, 1999). Specifically, the kinase reactionsolution was transferred to a 96-well black half-plate (Product No.3694, Coster, Inc.), 7.5 ng of europium cryptate-labeledanti-phosphotyrosine antibody (Eu(K)-PY20, purchased from CISDiagnostics Co.) (25 μl of a 250-fold dilution with 20 mM Hepes (pH7.0), 0.5 M KF, 0.1% BSA solution) and 250 ng of XL665-labeledstreptavidin (XL665-SA, purchased from CIS Diagnostics Co.) (25 μl of a62.5-fold dilution with 20 mM Hepes (pH 7.0), 0.5 M KF and 0.1% BSAsolution) were added thereto, the mixture was allowed to stand at roomtemperature for 30 minutes, and then the fluorescent intensity wasmeasured at 665 nm and 620 nm under irradiation with an excitationwavelength of 337 nm using a Discovery HTRF Microplate Analyzer (PackardCo.). The tyrosine phosphorylation rate for the biotin-poly(GT) wasexpressed as the delta F % value as described in the HTRF StandardExperiment Methods text by CIS Diagnostics Co. The delta F % value inthe presence of the test substance was determined as a ratio (%) withthe delta F % value with addition of His6-VEGFR2 in the absence of thetest substance defined as 100% and the delta F % value in the absence ofboth the test substance and His6-VEGFR2 defined as 0%. This ratio (%)was used to calculate the test substance concentration required for 50%inhibition of VEGFR2 kinase activity (IC₅₀).

Measurement of inhibition against FGFR1, EGFR and HGFR kinase activitywas conducted using 15 ng of His6-FGFR1, 23 ng of EGFR and 30 ng ofHis6-HGFR, respectively, according to the tyrosine kinase reaction andHTRF method described above.

Measurement of inhibition against PDGFRβ kinase activity was conductedusing 50 ng of His6-PDGFRβ according to the tyrosine kinase reactiondescribed above, followed by detection of tyrosine phosphorylatedbiotin-poly(GT) by the following method.

Specifically, the kinase reaction solution was added to a 96-wellstreptavidin-coated plate (Product No. 15129, Pierce Chemical) andincubated at room temperature for 30 minutes. After rinsing 3 times with150 μl of a rinsing solution {20 mM Tris-HCl (pH 7.6), 137 mM NaCl,0.05% Tween-20, 0.1% BSA}, 70 μl of anti-phosphotyrosine (PY20)-HRPconjugate (Product No. P-11625, Transduction Laboratories) {2000-folddilution with 20 mM Tris-HCl (pH 7.6), 137 mM NaCl, 0.05% Tween-20, 1%BSA} was added thereto and incubation was performed at room temperaturefor 1 hour. After incubation, it was rinsed 3 times with 150 μl of therinsing solution, and 100 μl of TMB Membrane Peroxidase Substrate(Product No. 50-5077-03, Funakoshi Co., Ltd.) was added to initiate thereaction. After stationing at room temperature for 10 minutes, 100 μl of1 M phosphoric acid was added to suspend the reaction, and theabsorbance at 450 nm was measured with a microplate reader (BIO KINETICSREADER EL304, Bio-Tek Instruments). The absorbance ratio in the presenceof the test substance was determined with respect to 100% as theabsorbance with addition of His6-PDGFRβ and no test substance, and 0% asthe absorbance without addition of the test substance or His6-PDGFRβ.This absorbance ratio was used to calculate the test substanceconcentration required for 50% inhibition of PDGFRβ kinase activity(IC₅₀).

TABLE 3 [Pharmacological Test Example 3: Inhibition against VEGFR2kinase] Example No. IC₅₀ (nM) Example No. IC₅₀ (nM) 1 51 10 4.9 14 2.715 8.7 21 4.3 30 22 31 17 33 6.9 34 3.4 25 5.5 36 14 37 22 43 18 54 1555 29 65 15 99 8.6 100 9.6 111 21 116 4.2 121 8.7 143 70 159 25 173 356178 12 182 71 183 29 184 59 187 14 208 9.2 252 31 253 23 259 16 260 11262 9.5 265 6.2 266 5.4 283 26 314 5.3 316 6.4 346 4.6 348 4.6 350 43353 2.2 356 1.4 364 8.1 365 5.4 368 3.0 374 8.4 375 16 381 2.6 382 9.0387 4.1 394 15 398 3.5 404 6.5 410 2.2 413 3.2 435 22 437 9.9 441 2.8449 2.2 463 5.9 465 13 556 14

Pharmacological Test Example 4 Inhibition on Cancer Cell and Normal CellGrowth

Cancer cells (for example, KP-4 human pancreatic cancer cells) or normalcells (for example, IEC-18 rat ileal epithelial cells) were subculturedin RPMI 1640 medium containing 10% FBS (purchased from NissuiPharmaceutical Co., Ltd.) every 3-4 days, and cells in the growth phasewere used. After recovering the cells using trypsin-EDTA, the cells werecounted and a 0.1 ml cell suspension of each diluted with 10%FBS-containing RPMI 1640 medium (to 2×10³ cells/well for KP-4 and 8×10²cells/well for IEC18) was spread onto a 96-well plate for cellculturing. Culturing was performed overnight in a 5% CO₂ incubator (37°C.), and then a 0.1 ml solution of the test substance diluted with 10%FBS-containing RPMI 1640 was added and culturing was continued in a 5%CO₂ incubator (37° C.). On the 3rd day after addition of the testsubstance, 0.05 ml of a 3.3 mg/ml MTT solution (purchased from SigmaCo.) was added, and culturing was continued in the 5% CO₂ incubator (37°C.) for approximately 2 hours. After aspirating off of the culturesupernatant and DMSO dissolution of the formazan produced in each well,the absorbance of each well was measured using an MTP-32 plate reader(Corona Electric) at a measuring wavelength of 540 nm and a referencewavelength of 660 nm. The absorbance ratio in the substance-added wellwas determined as a percentage with respect to the absorbance of thewell without addition of the test substance, and this ratio was used tocalculate the test substance concentration required for 50% inhibitionof cell growth (IC₅₀).

Pharmacological Test Example 5 Effect of L6 (Rat Myoblasts) onPDGF-Dependent Growth

L6 (rat myloblasts) were subcultured in 10% FBS-containing D-MEM medium(purchased from Nissui Pharmaceutical Co., Ltd.) every 3-4 days, andcells in the growth phase were used. The cells were recovered usingtrypsin-EDTA and rinsed once with 10% FBS-free D-MEM medium, and thecells were counted. After spreading 0.1 ml of a cell suspension dilutedwith 10% FBS-free D-MEM medium onto a Type I collagen-coated 96-welltissue culturing plate at 5×10³ cells/well, culturing was performedovernight in a 5% CO₂ incubator (37° C.). On the following day, 0.05 mlof a solution of the test substance diluted with 10% FBS-free D-MEMmedium was added, with almost simultaneous addition of 0.05 ml of a 40nM PDGF solution (10 nM final concentration), and culturing wascontinued in the 5% CO₂ incubator (37° C.). On the 3rd day afteraddition of the test substance, 0.01 ml of WST-1 solution (purchasedfrom Wako Pure Chemical Industries Co., Ltd.) was added to each well,and culturing was continued in the 5% CO₂ incubator (37° C.) forapproximately 3 hours until coloration. The absorbance of each well wasmeasured using an MTP-32 plate reader (Corona Electric) at a measuringwavelength of 415 nm and a reference wavelength of 660 nm. Theabsorbance ratio in the substance-added well was determined as apercentage with respect to the absorbance of the well without additionof the test substance, and this ratio was used to calculate the testsubstance concentration required for 50% inhibition of cell growth(IC₅₀).

Pharmacological Test Example 6 Analysis of mRNA Expression by DNAMicroarray/Quantitative PCR

1. Extraction of Total RNA from Sample

The cells were cultured at 37° C. either in 5% CO₂ or under low (1%)oxygen conditions. In the case of HUVEC, for example, EGM-2 medium(purchased from Clonetics Corp.) was used for culturing at 37° C. under5% CO₂ conditions. At a prescribed time after reaction with the testsubstance, the cells were lysed using TRIZOL reagent (purchased fromGIBCO BRL) according to the manufacturer's protocol. Specifically, itwas accomplished as follows. A 1 ml portion of TRIZOL reagent is addedper 10 cm² culturing area, and pipetting is carried out several times tocollect the cells. After centrifuging the sample, the obtainedsupernatant is allowed to stand at room temperature for 5 minutes, andthen chloroform (purchased from Junsei Chemical Co., Ltd.) is added in aproportion of 0.2 ml with respect to 1 ml of TRIZOL reagent used. Thesolution is vigorously shaken and stirred for 15 seconds and allowed tostand at room temperature for 2-3 minutes, and then centrifuged(12,000×g, 10 min, 4° C.). After centrifugation, the aqueous layer istransferred to a fresh tube, isopropyl alcohol (purchased from Wako PureChemical Industries Co., Ltd.) is added in a proportion of 0.5 ml to 1ml of TRIZOL reagent used, and the mixture is allowed to stand at roomtemperature for 10 minutes and then centrifuged (12,000×g, 10 min, 4°C.). The obtained precipitate is rinsed with 75% ethanol (purchased fromWako Pure Chemical Industries Co., Ltd.) and then air-dried and suppliedas total mRNA for the following procedure.

2. Quantitation of RNA

The RNA may be quantitated by techniques such as Northern blottinganalysis, DNA microarray, RT-PCR, quantitative PCR and the like, withDNA microarray and quantitative PCR being preferred. Explanations ofthese techniques are provided below, but are not intended to belimitative on the invention.

1) Quantitation with a DNA microarray (Schena M. et al., Science, 270(5235), 467-70, 1995 and Lockhart, D. J. et al., Nature Biotechnology,14 (13), 1675-1680, 1996) is carried out in the following manner.

[1] cDNA Synthesis and Biotin Labeling

The initially obtained RNA was used as template to synthesizedouble-stranded cDNA with a SuperScript Choice System (purchased fromGIBCO BRL) and T7-d(T)₂₄ primer, and then this cDNA was used as templatefor synthesis of biotinylated cRNA.

Specifically, 5 μg T7-d(T)₂₄ primer, 1×first strand buffer, 10 mM DTT,500 μM dNTP mix and 20 unit/μl SuperScript II Reverse Transcriptase wereadded to 10 μg of RNA, and reaction was conducted at 42° C. for 1 hourto synthesize single-stranded cDNA. Next, 1×second strand buffer, 200 μMdNTP mix, 67 U/ml DNA ligase, 270 U/ml DNA polymerase I and 13 U/mlRNaseH were added and reaction was conducted at 16° C. for 2 hours tosynthesize double-stranded cDNA. Finally, 67 U/ml T4 DNA polymerase Iwas added for reaction at 16° C. for 5 minutes, after which 10 μl of0.5M EDTA (purchased from Sigma Co.) was added to suspend the reaction.

The obtained cDNA was purified with phenol/chloroform (purchased fromAmbion, Inc.), and an RNA Transcript Labeling Kit (purchased from EnzoDiagnostics, Inc.) was used for labeling with biotinylated UTP and CTPaccording to the manufacturer's protocol. The reaction product waspurified with an RNeasy column (purchased from Qiagen), and then heatingwas performed for 35 minutes at 94° C. in 200 mM Tris acetate (pH 8.1),150 mM magnesium acetate and 50 mM potassium acetate, for fragmentationof the cRNA.

[2] DNA Microarray (GeneChip) Hybridization and Measurement

The fragmented cRNA is hybridized with a GeneChip (purchased fromAffymetrix Corp.) Hu6800/Human Cancer G110 Array or an equivalentproduct, in 100 mM MES, 1M sodium salt, 20 mM EDTA, 0.01% Tween20, forexample, at 45° C. for 16 hours. After hybridization, the GeneChip isrinsed and dyed according to protocol EukGE-WS2 included with theAffymetrix fluidics station or the optimum protocol for the array used.The dyeing is carried out using streptavidin-phycoerythrin (purchasedfrom Molecular Probe) and biotinylated anti-streptavidin goat antibody(purchased from Vector Laboratories). The dyed GeneChip is scanned usingan HP argon-ion laser confocal microscope (purchased from HewlettPackard Co.), and the fluorescent intensity is measured. Thefluorescence was measured with excitation at 488 nm and emission at 570nm.

All of the quantitative data analysis was carried out using GeneChipsoftware (purchased from Affymetrix Corp.) or Genespring (purchased fromSilicon Genetics). For RNA quantitation, the average of the difference(perfect match hybridization signal—mismatch signal) is determined foreach probe family, and the gene expression is judged as havingsignificantly “increased” or “decreased” if the value is 5 or greaterand the RNA quantities are disparate under 2 conditions, and preferablyif they are disparate by a factor of 1.8 or greater.

2) Quantitation by quantitative PCR is conducted in the followingmanner.

Quantitative PCR is accomplished in the following manner using SYBRGreen (purchased from Applied Biosystems) and an ABI Prism 7700 SequenceDetection System (purchased from Perkin-Elmer Applied Biosystems) or anequivalent apparatus.

The procedure is carried out by the two stages of reverse transcriptionand PCR reaction. In the reverse transcription of the first stage, dNTP,oligo d(T)₁₆ primer, RNase Inhibitor and Multiscribe ReverseTranscriptase (purchased from Perkin-Elmer Applied Biosystems) are addedto the obtained RNA, the temperature is kept at 25° C. for 10 minutes,and then heating is effected at 48° C. for 30 minutes. The reaction issuspended by heating at 95° C. for 5 minutes.

The obtained cDNA is then supplied to the PCR reaction of the secondstage. The PCR reaction is carried out in a reaction system comprising,for example, 4 ng cDNA, 1×SYBR PCR buffer, 3 mM MgCl₂, 200 μM each dATP,dCTP and dGTP, 400 μM dUTP, 200 nM primer pair, 0.01 U/μl AmpErase UNGand 0.025 U/μl Ampli Taq Gold DNA Polymerase (purchased fromPerkin-Elmer Applied Biosystems). The reaction was conducted underconditions with 50° C. for 2 minutes and 95° C. for 10 minutes followedby 40 cycles of 95° C. for 20 seconds, 55° C. for 20 seconds and 72° C.for 30 seconds. The primers and probes are designed using PrimerExpression (purchased from Perkin-Elmer Applied Biosystems) orequivalent software. The different test substances are compared whilecompensating the quantitative values based on the mRNA level of ahousekeeping gene having low transcription level fluctuation, preferablyGAPDH, in each specimen.

Pharmacological Test Example 7 Evaluation of In VivoAngiogenesis-Inducing Activity using Mouse Dorsal Air Sac Model

[1] Construction of VEGF (Vascular Endothelial Growth Factor) ExpressionVector

PCR was conducted using a human placenta cDNA library (purchased fromToyobo Co., Ltd.) as the template and the VEGF sequences5′CCGGATCCATGAACTTTCTGCTG3′ (SEQ ID NO: 1) and 5′GTGAATTCTGTATCGATCGTT3′ (SEQ ID NO: 2) as primers. After completion ofthe PCR reaction, the 5′ ends were phosphorylated and an approximately600 bp DNA band was separated by 1.2% agarose gel electrophoresis. Afterpolymerization by self-ligation, the cDNA was cut with EcoRI and BamHIand inserted into the EcoRI and BamHI sites of vector pUC19. This wasused to transform E. coli JM83, and plasmids were recovered from thetransformed clones. A VEGF cDNA fragment was cut out of the plasmidswith HindIII and EcoRI and then inserted into an expression vectorcontaining the neomycin resistance gene.

[2] Preparation of VEGF High-Expressing Strain

After overnight culturing of KP-1 human pancreatic cancer cells (3×10⁶cells) with 10% FCS-containing RPMI 1640 medium, an EffecteneTransfection Reagent Kit (purchased from Qiagen) was used forintroduction of 3 μg of VEGF expression vector into the KP-1 cells.After culturing in 10% FCS-containing RPMI 1640 medium also containing600 μg/ml of Geneticin, the high-expressing drug-resistant cells wereselected as VEGF high-expressing KP-1 cells (KP-1/VEGF).

[3] Measurement of VEGF Level in Culture Supernatant

The KP-1/VEGF cells were prepared to 5×10⁵ cells/ml, and 0.5 ml thereofwas dispensed into each well of a 24-well plate and cultured at 37° C.for 24 hours. The culture supernatants were collected and the VEGFlevels thereof measured using a VEGF measuring kit (purchased from IBLCo., Ltd.) for confirmation of high expression.

[4] Evaluation of In Vivo Angiogenesis-Inducing Activity using MouseDorsal Air Sac Model

Millipore rings (purchased from Nihon Millipore) were sealed with 0.45μm Durapore™ filter membranes (purchased from Nihon Millipore) to createchambers. KP-1/VEGF human pancreatic cancer cells (3×10⁶) suspended in0.17 ml of collagen gel were injected into each chamber through theinjection port, and the chambers were sealed. Approximately 10 ml of airwas then injected in the dorsal skin of 6-week-old C57BL/6N female miceunder anesthesia to produce pouches, and the prepared chambers weretransplanted therein. About 6 hours after completing transplantation, atest substance suspended in 0.5% methyl cellulose was orallyadministered (0.1 ml/10 g body weight), and this was continued once aday for the next 4 days.

On the 4th day after transplanting the chambers, 0.2 ml of ⁵¹Cr(Amersham Pharmacia)—labeled mouse erythrocytes (2.5×10⁶ cpm/ml) wereinjected through the caudal veins of each of the mice with thetransplanted chambers. After a prescribed period, the skin in contactwith the chamber was excised and frozen, the section in direct contactwith the chamber was precisely cut off, and the radioactivity wasmeasured with a γ-counter. The blood volume was calculated from theradioactivity and used as an index of the in vivo angiogenesis-inducingactivity. The angiogenesis volume was recorded as this measured bloodvolume minus the blood volume obtained with transplantation of a chambercontaining only collagen gel. The experiment was conducted using 10 micein the control (solvent-administered) group and 5 mice in eachcompound-administered group.

Pharmacological Test Example 8 Evaluation of Antitumor Activity onKP-1/VEGF Cells in Subcutaneous Xenograft Models

VEGF high-expressing pancreatic cancer cells (KP-1/VEGF) suspended inPBS at a concentration of 1×10⁷ cells/ml were transplanted under theright flank skin of 6-week-old female Balb/c (nu/nu) mice in a volume of0.1 ml. When the tumor volume reached approximately 100 mm³, the testsubstance was orally administered over a period of 2 weeks with aschedule of 5 days per week. The test substance was suspended in 0.5%methyl cellulose for an administered volume of 0.1 ml/10 g body weight.The tumor size was measured twice a week using a micrometer caliper. Thetumor volume was determined by measuring the long and short diameters ofthe tumor with a micrometer caliper, and calculating 1/2×(longdiameter×short diameter×short diameter). The experiment was conductedusing 10 mice in the control (solvent-administered) group and 5 mice ineach test substance-administered group.

Pharmacological Test Example 9 Evaluation of Tumor Growth, CancerousAscites Accumulation and Survival Period in Orthotopic TransplantationModels of Pancreatic Cancer

After abdominal section of 6- to 7-week-old female Balb/c (nu/nu) miceunder anesthesia and exposure of the pancreases, VEGF high-expressingpancreatic cancer cells (KP-1/VEGF) suspended in PBS at a concentrationof 1×10⁷ cells/ml were directly transplanted into each pancreas head ata volume of 0.1 ml. Upon the 4th week after transplantation, the testsubstance was orally administered over a period of 10 weeks with aschedule of 5 days per week. The test substance was suspended in 0.5%methyl cellulose for an administered volume of 0.1 ml/10 g body weight.Body weight was periodically measured twice per week during the testperiod, and the presence of ascites accumulation was recorded based onappearance. The survival period was based on tabulating the number ofmice which died up until completion of the experiment. Tumor weight wasmeasured in individuals suitable for postmortem autopsy. The experimentwas conducted using 8 to 10 mice per group.

INDUSTRIAL APPLICABILITY

According to the present invention, it is possible to provide novelcompounds that exhibit (1) powerful inhibiting action against invasivetube formation by vascular endothelial cells induced by an angiogenicfactor mixture comprising Epidermal Growth Factor (EGF)/VEGF/FibroblastGrowth Factor 2 (FGF2)/Hepatocyte Growth Factor (HGF)/Tumor NecrosisFactor alpha (TNF-α), (2) powerful inhibiting action against tubeformation by vascular endothelial cells specifically induced by singleangiogenic factors (for example, VEGF, FGF, HGF and other such factors),and 3) powerful inhibiting action against receptor kinases for variousangiogenic factors. It is further possible to provide novel compoundswhich are highly useful as medicines.

Among the group of compounds with the action of (1) to (3) describedabove there may also be provided a group of compounds with tumor cellgrowth-inhibiting action.

Incidentally, angiogenesis in the body is known to depend not on asingle angiogenic factor but rather on the additive and synergisticeffect of multiple angiogenic factors ((1) Koolwijk P, van Erck M G M,de Vree W J A, Vermeer M A, Weich H A, Hane maaijer R, van Hinsbergh V WM. Cooperative effect of TNF-alpha, bFGF and VEGF on the formation oftubular structures of human microvascular endothelial cells in a fibrinmatrix. Role of urokinase activity. J. Cell Biol. 1996, 132,P1177-1188.; (2) Tallquist M D, Soriano P, Klinghoffer R A. Growthfactor signaling pathways in vascular development. Oncogene 1999, 18,P7917-7932.).

Thus, the compounds of the invention which inhibit tube formationinduced by multiple angiogenic factors produced by cancer cells and thelike are expected to exhibit powerful angiogenesis inhibition in vivo,and should be highly useful as angiogenesis inhibitors. Moreover, thecompounds of the invention may be useful as prophylactic or therapeuticagents for diseases for which angiogenesis inhibition is effective, andspecifically as angiogenesis inhibitors, antitumor agents, angiomatreatment agents, cancer metastasis inhibitors, retinalneovascularization treatment agents, diabetic retinopathy treatmentagents, general inflammatory disease treatment agents, inflammatorydisease treatment agents for deformant arthritis, rheumatoid arthritis,psoriasis, delayed hypersensitivity reaction and the like, oratherosclerosis treatment agents, and particularly as antitumor agents,based on their angiogenesis inhibition.

EXAMPLES

The present invention will now be explained in further and more concretedetail through the following examples, with the implied understandingthat these examples are in no way limitative on the invention.

PRODUCTION EXAMPLES Production Example 12-(3-Chloropropyl)-1,2,3-triazole (Production Example 1-A)1-(3-Chloropropyl)-1,2,3-triazole (Production Example 1-B)

A suspension of sodium hydride (1.55 g, 30.8301 mmol, 60% in oil) inhexane was allowed to stand, and after removing the supernatant,dimethylformamide (25 ml) was added thereto to forma suspension and1H-1,2,3-triazole (1.5 ml, 25.8867 mmol) was added dropwise whilecooling on ice. This was stirred at room temperature for 5 minutes tothorough dissolution, and then 1-bromo-3-chloropropane (2.82 ml, 28.4754mmol) was added and the mixture was stirred at room temperature for 8hours. After adding water while cooling on ice, the mixture wasextracted with diethyl ether and then with ethyl acetate, washed withsaturated brine and dried over anhydrous magnesium sulfate, the solventwas distilled off under reduced pressure, and the isomers were separatedby NH silica gel column chromatography (hexane-ethyl acetate) andpurified to obtain low polarity 2-(3-chloropropyl)-1,2,3-triazole (0.429g, 2.9466 mmol, 11.38%) and high polarity1-(3-chloropropyl)-1,2,3-triazole (0.910 g, 6.2504 mmol, 24.15%) ascolorless oils.

2-(3-chloropropyl)-1,2,3-triazole (Production Example 1-A)

¹H-NMR Spectrum (CDCl₃) δ (ppm): 2.42 (2H, tt, J=6.4 Hz, 6.4 Hz), 3.54(2H, t, J=6.4 Hz), 4.64 (2H, t, J=6.4 Hz), 7.61 (2H, s).

1-(3-chloropropyl)-1,2,3-triazole (Production Example 1-B)

¹H-NMR Spectrum (CDCl₃) δ (ppm): 2.41 (2H, m), 3.52 (2H, d, J=6.0 Hz),4.60 (2H, d, J=6.4 Hz), 7.61 (1H, d, J=0.8 Hz), 7.72 (1H, d, J=0.8 Hz).

Production Example 2 1-Chloro-3-(4-pyridyl)propane

3-(4-Pyridyl)-1-propanol (2.68 g, 19.3724 mmol) was dissolved indichloromethane (100 ml), triphenylphosphine (5.6 g. 21.3096 mmol) wasadded, and then N-chlorosuccinimide (2.6 g, 19.3724 mmol) was graduallyadded while cooling on ice prior to stirring overnight. After distillingoff the solvent under reduced pressure, the residue was dissolved inethyl acetate and extracted with 1N hydrochloric acid. Uponneutralization with saturated sodium bicarnobate water, the mixture wasextracted with ethyl acetate, washed with saturated brine and dried overanhydrous magnesium sulfate, and the solvent was distilled off underreduced pressure to obtain the title compound (2,375 g, 15.2605 mmol,78.77%) as a yellowish-brown oil. This was used without furtherpurification for the following reaction.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 2.11 (2H, m), 2.80 (2H, t, J=7.6 Hz),3.54 (2H, t, J=6.4 Hz), 7.14 (2H, dd, J=1.6 Hz, 4.4 Hz), 8.52 (2H, dd,J=1.6 Hz, 4.4 Hz).

Production Example 3 4-Amino-3-fluorophenol

3-Fluoro-4-nitrophenol (5.0 g, 31.83 mmol) was dissolved in ethylacetate (50 ml) and tetrahydrofuran (75 ml), and then palladium carbon(2.0 g) was added and the mixture was stirred for 8.5 hours at roomtemperature under a hydrogen atmosphere. The catalyst was filtered off,the filtrate was washed with ethanol, the solvent was distilled offunder reduced pressure and the obtained crystals were washed withaddition of hexane:ethanol=1:1. The crystals were filtered out, washedwith diethyl ether and dried by aspiration to obtain the title compound(1.62 g, 12.74 mmol, 40.61%) as light yellow crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 4.35 (1H, brs), 6.32 (1H, dd, J=2.4Hz, 8.4 Hz), 6.39-6.45 (1H, m), 6.57 (1H, dd, J=8.4 Hz, 10.4 Hz).

Production Example 4N-(2,4-Difluorophenyl)-N′-(2-fluoro-4-hydroxyphenyl)urea

4-Amino-3-fluoronitrophenol (500 mg, 3.9333 mmol) was dissolved intetrahydrofuran (15 ml), 2,4-difluoro isocyanate (0.56 ml, 4.7199 mmol)was added dropwise, and the mixture was heated to reflux for 1 hourunder a nitrogen atmosphere. After allowing the mixture to cool, thesolvent was distilled off under reduced pressure, and the obtainedcrystals were washed with addition of hexane:ethanol=1:1. The crystalswere filtered out, washed with hexane:ethanol=1:1 and dried byaspiration to obtain the title compound (960 mg, 3.4016 mmol, 86.48%) aslight violet crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 6.54 (1H, m), 6.60 (1H, ddd, J=2.4Hz, 2.4 Hz, 8.8 Hz), 7.00 (1H, m), 7.27 (1H, ddd, J=2.8 Hz, 9.0 Hz, 11.6Hz), 7.69 (1H, m), 8.07 (1H, ddd, J=6.0 Hz, 9.0 Hz, 9.0 Hz), 8.53 (1H,s), 8.72 (1H, s), 9.56 (1H, s).

Production Example 5 7-Benzyloxy-6-cyano-4-(4-nitrophenoxy)quinoline

To the 7-benzyloxy-4-chloro-6-cyanoquinoline (2.60 g, 8.83 mmol)described in WO98/13350 there were added 4-nitrophenol (2.46 g, 17.7mmol) and lutidine (2.06 ml, 17.7 mmol), and the mixture was heated andstirred at 155-158° C. for 2 hours. After returning the reaction systemto room temperature, it was dissolved in tetrahydrofuran, saturatedsodium bicarnobate water was added and stirred therewith for 10 minutes,the mixture was concentrated under reduced pressure, the precipitatedsolid was filtered out and subjected to silica gel column chromatography(Fuji Silysia NH Type, eluent—hexane:ethyl acetate=50:50→ethyl acetatealone), the fraction containing the target substance was concentratedand the obtained solid was washed with diethyl ether. It was then driedunder reduced pressure to obtain the title compound (1.84 g, 4.63 mmol,52.6%).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 5.48 (2H, s), 6.89 (1H, d, J=6.1 Hz),7.30-7.60 (8H, m), 7.78 (1H, s), 8.36-8.41 (2H, m), 8.80 (1H, s), 8.85(1H, d, J=6.1 Hz).

Production Example 6 4-(4-Aminophenoxy)-7-(benzyloxy)-6-cyanoquinoline

Iron powder (0.6 g), ammonium chloride (1.4 g), ethanol (100 ml) andwater (30 ml) were added to the7-benzyloxy-6-cyano-4-(4-nitrophenoxy)quinoline obtained in ProductionExample 5, and the mixture was stirred at 90° C. for 2.5 hours. Thereaction system was returned to room temperature and then filtered withcelite, the filtrate was subjected to liquid separation, and the organiclayer was washed with water and saturated brine in that order, driedover sodium sulfate and then concentrated to dryness under reducedpressure to obtain 1.31 g of a crude product containing the targetsubstance. The crude product was used directly for the followingreaction. (Production Example 7).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 3.75 (2H, br), 5.35 (2H, s), 6.46 (1H,d, J=5.2 Hz), 6.75-6.78 (2H, m), 6.94-6.97 (2H, m), 7.35 (1H, d, J=7.6Hz), 7.42 (2H, t, J=6.8 Hz), 7.50-7.55 (3H, m), 8.63 (1H, d, J=5.2 Hz),8.72 (1H, s).

Production Example 77-Benzyloxy-6-cyano-4-(3-fluoro-4-nitrophenoxy)quinoline

The 7-benzyloxy-4-chloro-6-cyanoquinoline (8.82 g, 30.0 mmol) describedin WO98/13350 was suspended in 1-methylpyrrolidone (30 ml), and then3-fluoro-4-nitrophenol (5.18 g, 33.0 mmol) and N,N-diisopropylethylamine(3.88 g, 30.0 mmol) were added and the mixture was heated and stirred at110° C. for 4 hours. After returning the reaction system to roomtemperature, water was added and a solid precipitated. The obtainedsolid was filtered out, washed with water, methanol and ethyl acetateand dried at 60° C. to obtain the title compound (4.98 g, 12.0 mmol,40%) as colorless crystals.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 5.37 (2H, s), 6.73 (1H, d, J=5.2 Hz),7.07-7.13 (2H, m), 7.33-7.45 (3H, m), 7.50-7.56 (2H, m), 7.60 (1H, s),8.21-8.27 (1H, m), 8.55 (1H, s), 8.83 (1H, d, J=5.2 Hz).

Production Example 87-Benzyloxy-6-cyano-4-(3-fluoro-4-aminophenoxy)quinoline

The 7-benzyloxy-6-cyano-4-(3-fluoro-4-nitrophenoxy)quinoline (5.30 g,12.8 mmol) obtained in Production Example 7, iron (3.57 g, 64.0 mmol)and ammonium chloride (6.85 g, 128 mmol) were suspended in an ethanol(120 ml)-water (30 ml) mixed solvent, and the suspension was heated andstirred at 100° C. for 3 hours. After completion of the reaction, thereaction mixture was filtered with celite and washed in an ethyl acetate(500 ml)-N,N-dimethylformamide DMF (50 ml) mixed solvent. The organiclayer was washed with water and saturated brine, dried over magnesiumsulfate and concentrated. The obtained solid was recrystallized from anethyl acetate-hexane mixed solvent and then dried to obtain the titlecompound (2.53 g, 6.56 mmol, 51%) as light brown crystals.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 3.80 (2H, brs), 5.35 (2H, s), 6.48 (1H,d, J=5.3 Hz), 6.78-6.90 (3H, m), 7.32-7.44 (3H, m), 7.51 (1H, s),7.52-7.56 (2H, m), 8.66 (1H, d, J=5.3 Hz), 8.69 (1H, s).

Production Example 96-Cyano-7-(2-methoxyethoxy)-4-(4-nitrophenoxy)quinoline

A mixture of 4-chloro-6-cyano-7-(2-methoxyethoxy)quinoline (3 g),4-nitrophenol (3.17 g) and 2,6-lutidine (2.7 ml) was heated and stirredin an oil bath at 155° C. for 1.5 hours. After completion of thereaction, ethyl acetate was added, and the precipitated solid wasfiltered out. The solid was washed with 1N sodium hydroxide water andthen with water and dried to obtain 1.8 g of the title compound.

¹H-NMR (DMSO-d₆) δ (ppm): 3.36 (3H, s), 3.76-3.79 (2H, m), 4.41-4.44(2H, m), 6.85 (1H, d, J=5.2 Hz), 7.54 (2H, d, J=9.2 Hz), 7.68 (1H, s),8.37 (2H, d, J=9.2 HZ), 8.74 (1H, s), 8.83 (1H, d, J=5.2 Hz).

Production Example 104-(4-Aminophenoxy)-6-cyano-7-(2-methoxyethoxy)quinoline

6-Cyano-7-(2-methoxyethoxy)-4-(4-nitrophenoxy)quinoline (1.8 g), iron(1.8 g) and ammonium chloride (3.6 g) were suspended in an ethanol (30ml)-water (7 ml) mixed solvent and the suspension was heated and stirredat 80° C. for 2 hours. After completion of the reaction, the reactionmixture was filtered with celite and washed in ethyl acetate. Theorganic layer was washed with saturated brine, dried over magnesiumsulfate and concentrated. The obtained solid was washed with ether anddried to obtain 1.2 g of the title compound.

¹H-NMR (DMSO-d₆) δ (ppm): 3.36 (3H, s), 3.75-3.78 (2H, m), 4.38-4.41(2H, m), 5.19 (2H, brd), 6.45 (1H, d, J=5.2 Hz), 6.65 (2H, d, J=8.8 Hz),6.93 (2H, d, J=8.8 Hz), 7.59 (1H, s), 8.68 (1H, d, J=5.2 HZ), 8.71 (1H,s).

Production Example 116-Cyano-4-(3-fluoro-4-nitrophenoxy)-7-(2-methoxyethoxy)quinoline

4-Chloro-6-cyano-7-(2-methoxyethoxy)quinoline (1.7 g) and3-fluoro-4-nitrophenol (2.0 g) were suspended in chlorobenzene (20 ml),and the suspension was heated to reflux for 6 hours. After completion ofthe reaction, the solvent was distilled off, ethyl acetate was added,and a solid precipitated. The solid was filtered out and washed withether, washed with 1N sodium hydroxide water and with water, and thendried to obtain 1.55 g of the title compound.

¹H-NMR (DMSO-d₆) δ (ppm): 3.38 (3H, s), 3.78-3.81 (2H, m), 4.44-4.47(2H, m), 7.02 (1H, d, J=5.2 Hz), 7.33-7.37 (1H, m), 7.69 (1H, dd, J=2.8Hz, J=12 Hz), 7.72 (1H, s), 8.33 (1H, t, J=8.8 HZ), 8.75 (1H, s), 8.88(1H, d, J=5.2 Hz).

Production Example 124-(4-Amino-3-fluorophenoxy)-6-cyano-7-(2-methoxyethoxy)quinoline

The title compound (1.23 g) was obtained from the nitro compound (1.55g) obtained in Production Example 11, in the same manner as ProductionExample 10.

¹H-NMR (DMSO-d₆) δ (ppm): 3.38 (3H, s), 3.78-3.81 (2H, m), 4.42-4.44(2H, m), 5.25-5.27 (2H, brd), 6.54 (1H, d, J=5.2 Hz), 6.87-6.89 (2H, m),7.10-7.14 (1H, m), 7.62 (1H, s), 8.72 (1H, d, J=5.2 HZ), 8.74 (1H, s).

Production Example 13 6-Cyano-7-methoxy-4-(4-nitrophenoxy)quinoline

A mixture of 4-chloro-6-cyano-7-methoxyquinoline (0.35 g) obtained inthe same manner as Production Example 7, 4-nitrophenol (0.36 g) and2,6-lutidine (0.25 ml) was heated and stirred in an oil bath at 170° C.After completion of the reaction, water and ethyl acetate were added tothe reaction mixture for extraction. The organic layer was washed withan aqueous saturated sodium bicarnobate solution and saturated brine,dried over magnesium sulfate and concentrated. The obtained residue waspassed through an NH silica gel column (Fuji Silysia Chemical), elutedwith a solvent (ethyl acetate:hexane=1:2) and concentrated to obtain 0.2g of the title compound.

¹H-NMR (DMSO-d₆) δ (ppm): 4.06 (3H, s), 6.87 (1H, d, J=5.6 Hz), 7.54(2H, d, J=8.8 Hz), 7.65 (1H, s), 8.36 (2H, d, J=8.8 Hz), 8.75 (1H, s),8.84 (1H, d, J=5.6 Hz).

Production Example 14 4-(4-Aminophenoxy)-6-cyano-7-methoxyquinoline

The title compound (0.17 g) was obtained from6-cyano-7-methoxy-4-(4-nitrophenoxy)quinoline (0.2 g) in the same manneras Production Example 10.

¹H-NMR (DMSO-d₆) δ (ppm): 4.06 (3H, s), 5.15-5.20 (2H, m), 6.46 (1H, d,J=5.6 Hz), 6.66 (2H, d, J=8.8 Hz), 6.93 (2H, d, J=8.8 Hz), 7.56 (1H, s),8.69 (1H, d, J=5.6 Hz), 8.71 (1H, s).

Production Example 156-Cyano-4-(3-fluoro-4-nitrophenoxy)-7-methoxyquinoline

The title compound (0.33 g) was obtained from4-chloro-6-cyano-7-methoxyquinoline (0.5 g) obtained in the same manneras Production Example 7, in the same manner as Production Example 13.

¹H-NMR (DMSO-d₆) δ (ppm): 4.07 (3H, s), 7.00 (1H, d, J=5.2 Hz),7.30-7.34 (1H, m), 7.65 (1H, dd, J=2.8 Hz, J=12 Hz), 7.66 (1H, s), 8.30(1H, t, J=8.8 Hz), 8.72 (1H, s), 8.87 (1H, d, J=5.2 Hz).

Production Example 164-(4-Amino-3-fluorophenoxy)-6-cyano-7-methoxyquinoline

The title compound (0.24 g) was obtained from6-cyano-4-(3-fluoro-4-nitrophenoxy)-7-methoxyquinoline (0.32 g) in thesame manner as Production Example 10.

¹H-NMR (DMSO-d₆) δ (ppm): 4.06 (3H, s), 5.26 (2H, brs), 6.54 (1H, d,J=5.2 Hz), 6.85-6.91 (2H, m), 7.11 (1H, dd, J=2.0 Hz, J=11.2 Hz), 7.59(1H, s), 8.72 (1H, d, J=5.2 Hz), 8.73 (1H, s).

Production Example 17 PhenylN-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)carbamate

The 4-(4-aminophenoxy)-6-cyano-7-(2-methoxyethoxy)quinoline (3.354 g,10.0 mmol) obtained in Production Example 10 was dissolved indimethylformamide (35 ml) under a nitrogen atmosphere, and then thesolution was cooled in an ice water bath, pyridine (2.43 ml, 30.0 mmol)and phenyl chloroformate (1.38 ml, 11.0 mmol) were added in that order,and the mixture was stirred at room temperature for 3 hours. Water (40ml) was added to the reaction solution and the precipitated crystalswere filtered out. The filtrate was extracted with ethyl acetate, andthe organic layer was washed with water and saturated brine and driedover anhydrous sodium sulfate. The drying agent was filtered off, andthe crystals obtained by concentration under reduced pressure werecombined with the previous crystals, suspended in hexane-ethyl acetate(5:1) and stirred overnight, after which the crystals were filtered outand dried under reduced pressure to obtain the title compound (4.334 g,9.52 mmol, 95.2%) as light brown crystals.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 3.53 (3H, s), 3.91 (2H, t, J=4.4 Hz),4.38 (2H, t, J=4.4 Hz), 6.49 (1H, d, J=5.2 Hz), 7.07 (1H, br), 7.17-7.32(5H, m), 7.40-7.45 (2H, m), 7.44 (1H, s), 7.59 (2H, d, J=8.8 Hz), 8.67(1H, d, J=5.6 Hz), 8.70 (1H, s).

Production Example 18 PhenylN-(4-(6-cyano-7-(2-methoxyethoxy)-quinolyl)oxy-2-fluorophenyl)carbamate

The 4-(4-amino-3-fluorophenoxy)-6-cyano-7-(2-methoxyethoxy)quinoline(2500 mg) obtained in Production Example 12 was dissolved in 20 ml ofdimethylformamide and 1.7 ml of pyridine, and the solution was cooled to0° C. under a nitrogen atmosphere. After adding 0.97 ml of phenylchlorocarbonate to the solution, it was stirred at room temperature for2 hours. Ethyl acetate and water were added to the reaction solution fordistribution, and the organic layer was washed with water and saturatedbrine in that order, dried over anhydrous sodium sulfate and thenconcentrated under reduced pressure to obtain 3.7 g of a residue. Thiswas dissolved in tetrahydrofuran, and then n-hexane was added and theprecipitated solid was filtered out to obtain 2.2 g of the titlecompound as light brown crystals (67% yield).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 3.36 (3H, s), 3.89-3.94 (2H, m),4.34-4.39 (2H, m), 6.52 (1H, d, J=5.6 Hz), 7.01-7.06 (2H, m), 7.21-7.30(4H, m), 7.40-7.45 (2H, m), 7.49 (1H, s), 8.26 (1H, brs), 8.66 (1H, s),8.70 (1H, d, J=5.6 Hz).

Production Example 19 PhenylN-(4-(6-cyano-7-methoxy-4-quinolyl)oxyphenyl)carbamate

The 4-(4-aminophenoxy)-6-cyano-7-methoxyquinoline (747 mg) obtained inProduction Example 14 was dissolved in 7 ml of dimethylformamide and0.34 ml of pyridine, and the solution was cooled to 0° C. under anitrogen atmosphere. After adding 0.34 ml of phenyl chlorocarbonate tothe solution, it was stirred at room temperature for 2 hours. Ethylacetate and water were added to the reaction solution, and theprecipitated solid was filtered out to obtain 590 mg of the titlecompound as light brown crystals (56% yield).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 4.04 (3H, s), 6.52 (1H, d, J=5.6 Hz),7.20-7.30 (5H, m), 7.40-7.46 (2H, m), 7.60 (1H, s), 7.62-7.68 (2H, m),8.72 (1H, d, J=5.6 Hz), 8.75 (1H, s), 10.4 (1H, brs).

Production Example 20 6-Chloro-4-(4-nitrophenoxy)pyrimidine

After adding 4,6-dichloropyrimidine (750 mg) to a suspension of4-nitrophenol (700 mg) and sodium hydride (60%) (200 mg)indimethylformamide (13 ml) at 0° C., the mixture was heated and stirredat 80° C. for 1.5 hours. The reaction solution was poured into saturatedbrine and extracted with ethyl acetate. The organic layer was dried overmagnesium sulfate and then concentrated. The obtained residue was passedthrough an NH silica gel column (Fuji Silysia Chemical), eluted with asolvent (ethyl acetate-hexane=1-4) and concentrated to obtain 700 mg ofthe title compound.

¹H-NMR (DMSO-d₆) δ (ppm): 7.08 (1H, d, J=0.8 Hz), 7.30-7.37 (2H, m),8.32-8.36 (2H, m), 8.60 (1H, d, J=0.8 Hz).

Production Example 214-(4-Amino-3-fluorophenoxy)-7-hydroxyquinoline-6-carbonitrile

After adding 26 ml of trifluoroacetic acid and 2.6 ml of thioanisole to2.6 g of 7-benzyloxy-6-cyano-4-(3-fluoro-4-nitrophenoxy)quinoline 2.6 g,the mixture was stirred at 70-72° C. for 15 hours and returned to roomtemperature, and then the reaction system was concentrated, saturatedsodium bicarnobate water and methanol were added to the residue, and theprecipitated yellow crystals were filtered out. Drying yielded 2.61 g ofcrystals. To 640 mg of the crystals there were added 950 mg of iron, 1.8g of ammonium chloride, 10 ml of ethanol, 10 ml of tetrahydrofuran, and10 ml of water, the mixture was refluxed for 1 hour, the reaction systemwas filtered with celite, ethyl acetate and water were added to thefiltrate for liquid separation and extraction, and the organic layer wasconcentrated to dryness to obtain 355 mg of the title compound.

¹H-NMR Spectrum: (DMSOd₆) 5.22 (2H, s), 6.42 (1H, d, J=5.8 Hz),6.80-6.90 (2H, m), 7.08 (2H, d, J=12.0 Hz), 8.60-8.65 (2H, m), 11.60(1H, brs)

Production Example 22 Phenyl 3-methylsulfonylphenylcarbamate

1-Amino-3-methylthiobenzene (1.27 ml, 10 mmol) was dissolved intetrahydrofuran (10 ml), and then triethylamine (1.46 ml, 10.5 mmol) andphenyl chloroformate (1.32 ml, 10.5 mmol) were added dropwise in thatorder at room temperature under a nitrogen atmosphere and the mixturewas stirred overnight. The reaction solution was distributed betweenethyl acetate and water, and the organic layer was washed with saturatedbrine and dried over anhydrous sodium sulfate. After distilling off thesolvent and drying under reduced pressure, the residue was dissolved indichloromethane (50 ml), and 3-chloroperbenzoic acid (4.93 g, 20 mmol)was gradually added while cooling in an ice water bath. An aqueoussaturated solution of sodium thiosulfate was added to the reactionsolution, and then the insoluble portion was filtered off, andextraction with ethyl acetate was followed by washing with an aqueoussaturated solution of sodium carbonate and drying over anhydrous sodiumsulfate. The solvent was distilled off, and the residue was purified bysilica gel column chromatography (ethyl acetate-hexane=1:1) to obtainthe title compound (2.545 g, 8.74 mmol, 87.4%) as white crystals.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 3.07 (3H, s), 7.18-7.29 (4H, m),7.40-7.44 (2H, m), 7.55 (1H, t, J=8.0 Hz), 7.68 (1H, d, J=8.0 Hz), 7.80(1H, d, J=8.0 Hz), 8.05 (1H, s).

Production Example 234-[(2,2-Dimethyl-4,6-dioxo[1,3]dioxane-5-ylidenemethyl)-amino]-2-methoxybenzonitrile

4-Amino-2-chlorobenzonitrile (3 g) was dissolved in1-methyl-2-pyrrolidone (10 ml), and then sodium methoxide (2.12 g) wasadded and the mixture was heated and stirred for 7 hours at 100° C. Thereaction solution was poured into an aqueous saturated solution ofammonium chloride and extracted with ethyl acetate, and the organiclayer was dried over magnesium sulfate and concentrated. The obtainedresidue was subjected to NH silica gel column chromatography and elutedwith a solvent (ethyl acetate:n-hexane=1:2) to obtain an anilinecompound (1.26 g). The aniline compound (1.26 g) was heated to reflux inethanol together with ethoxymethylene-Meldrum acid (1.7 g). The solidwhich precipitated after 2 hours was filtered out, washed with ethanoland then dried to obtain the title compound (1.9 g).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.66 (6H, s), 3.94 (3H, s), 7.21-7.26(1H, m), 7.46-7.50 (1H, m), 7.72 (1H, d, J=8.4 Hz), 8.70 (1H, s).

Production Example 247-Methoxy-4-oxo-1,4-dihydroquinoline-6-carbonitrile

4-[(2,2-Dimethyl-4,6-dioxo[1,3]dioxane-5-ylidenemethyl)amino]-2-methoxybenzonitrile(1.9 g) was heated for cyclization in the same manner as ProductionExample 457-3, to obtain the title compound (1.08 g) as a solid.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.96 (3H, s), 6.02 (1H, d, J=7.6 Hz),7.06 (1H, s), 7.89 (1H, d, J=7.6 Hz), 8.30 (1H, s).

Production Example 256-Methoxycarbonyl-7-methoxy-4-(5-indolyloxy)quinoline

After mixing methyl 4-chloro-7-methoxyquinoline-6-carboxylate (describedin WO0050405, p. 34, 8.5 g, 33.77 mmol), 5-hydroxyindole (7 g),diisopropylethylamine (8.9 ml) and N-methylpyrrolidone (8.9 ml), themixture was heated and stirred at 130° C. for 5 hours and then at 150°C. for 8 hours. After standing to cool, the solution was adsorbed ontosilica gel and purified with a silica gel column (hexane-ethyl acetatesystem). Ethanol, diethyl ether and hexane were added to the obtainedyellow oil, and crystals precipitated after a period of standing. Thecrystals were filtered out, washed with diethyl ether and hexane andthen dried by aspiration to obtain light yellow crystals (3.506 g, 10.06mmol, 29.80%).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.86 (3H, s), 3.97 (3H, s), 6.38 (1H,d, J=5.2 Hz), 6.46 (1H, s), 6.98 (1H, d, J=8.8 Hz), 7.44-7.52 (4H, m),8.60-8.65 (2H, m), 11.29 (1H, s).

Production Example 267-(2-Methoxyethoxy)-4-oxo-1,4-dihydro-6-quinolinecarboxylic acid

The 7-methoxy-4-oxo-1,4-dihydroquinoline-6-carbonitrile (8.0 g)described in WO9813350 was used to obtain the title compound (6.3 g) bythe same procedure as in Production Example 152-1.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.33 (3H, s), 3.71-3.73 (2H, m),4.21-4.22 (2H, m), 6.28 (1H, d, J=7.2 Hz), 7.15 (1H, s), 8.59 (1H, d,J=7.2 Hz), 8.40 (1H, s)

EXAMPLES Example 1N-(4-(6-Cyano-7-(3-(4-pyridyl)propoxy)-4-quinolyl)oxyphenyl-N′-(4-methoxyphenyl)urea

The sodium6-cyano-4-(4-((4-methoxyanilino)carbonyl)aminophenoxy)-7-quinolinolate(200 mg) synthesized in Example 87 was dissolved in dimethylformamide (4ml), and then potassium carbonate (130 mg, 0.9400 mmol), potassiumiodide (3 mg) and 1-chloro-3-(4-pyridyl)propane (80 mg, 0.5159 mmol)were added and the mixture was heated and stirred at 80° C. for 5 hoursand 30 minutes. After allowing the mixture to stand and adding saturatedbrine, it was extracted with ethyl acetate, washed with saturated brineand dried over anhydrous magnesium sulfate, the solvent was distilledoff under reduced pressure, and the residue was purified by NH silicagel column chromatography (ethyl acetate-methanol system). The obtainedcrystals were suspended in ethanol, the suspension was diluted withdiethyl ether, and the crystals were filtered out, washed with diethylether and dried by aspiration to obtain the title compound (60 mg) aslight yellow crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.17 (2H, d), 2.84 (2H, t, J=7.8 Hz),3.70 (3H, s), 4.28 (2H, t, J=6.2 Hz), 6.51 (1H, d, J=5.2 Hz), 6.86 (2H,d, J=9.0 Hz), 7.22 (2H, d, J=9.0 Hz), 7.29 (2H, d, J=6.0 Hz), 7.35 (2H,d, J=9.0 Hz), 7.57 (1H, s), 7.58 (2H, d, J=9.0 Hz), 8.46 (2H, d, J=6.0Hz), 8.49 (1H, s), 8.71 (1H, d, J=5.2 Hz), 8.74 (1H, s), 8.76 (1H, s).

Example 2N-(4-(6-Cyano-7-(4-picolyloxy)-quinolyl)oxyphenyl)-N′-(4-methoxyphenyl)urea

The sodium6-cyano-4-(4-((4-methoxyanilino)carbonyl)aminophenoxy)-7-quinolinolate(100 mg) synthesized in Example 87 was dissolved in dimethylformamide (2ml), and then potassium carbonate (97 mg, 0.7018 mmol), potassium iodide(3 mg) and 4-picolyl chloride (40 mg, 0.2462 mmol) were added and themixture was heated and stirred at 80° C. for 3 hours. After allowing themixture to stand and adding water, it was extracted with ethyl acetate,washed with saturated brine and dried over anhydrous magnesium sulfate,the solvent was distilled off under reduced pressure, and the residuewas purified by NH silica gel column chromatography (ethylacetate-methanol system). The obtained crystals were suspended inacetone, the suspension was diluted with diethyl ether, and the crystalswere filtered out, washed with diethyl ether and dried by aspiration toobtain the title compound (30 mg) as light yellow crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.70 (3H, s), 5.54 (2H, s), 6.53 (1H,d, J=5.2 Hz), 6.86 (2H, d, J=8.8 Hz), 7.22 (2H, d, J=8.8 Hz), 7.36 (2H,d, J=8.8 Hz), 7.52 (2H, d, J=6.4 Hz), 7.59 (2H, d, J=8.8 Hz), 7.66 (1H,s), 8.55 (1H, brs), 8.63 (2H, d, J=6.0 Hz), 8.72 (1H, d, J=5.2 Hz), 8.81(1H, brs), 8.82 (1H, s).

Example 3N-(4-(6-Cyano-7-(3-picolyloxy)-4-quinolyl)oxyphenyl)-N′-(4-methoxyphenyl)urea

The sodium6-cyano-4-(4-((4-methoxyanilino)carbonyl)aminophenoxy)-7-quinolinolate(200 mg) synthesized in Example 87 was used for reaction in the samemanner as Example 2 to obtain the title compound (68 mg).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.70 (3H, s), 5.50 (2H, s), 6.54 (1H,d, J=5.0 Hz), 6.86 (2H, d, J=8.8 Hz), 7.22 (2H, d, J=8.8 Hz), 7.35 (2H,d, J=8.8 Hz), 7.49 (2H, dd, J=4.8 Hz, 7.6 Hz), 7.58 (2H, d, J=8.8 Hz),7.74 (1H, s), 7.95 (1H, d, J=7.6 Hz), 8.49 (1H, s), 8.59 (1H, dd, J=1.6,Hz, 4.8 Hz), 7.83-8.80 (3H, m).

Example 4N-(4-(6-Cyano-7-(2-(1,2,3-triazol-2-yl)ethoxy)-4-quinolyl)oxyphenyl)-N′-(4-fluorophenyl)urea(Example 4-A)N-(4-(6-Cyano-7-(2-(1,2,3-triazol-1-yl)ethoxy)-4-quinolyl)oxyphenyl)-N′-(4-fluorophenyl)urea(Example 4-B)

TheN-(4-(6-cyano-7-(2-chloroethoxy)-quinolyl)oxyphenyl)-N′-(4-fluorophenyl)urea(210 mg, 0.4403 mmol) synthesized in Example 90 was dissolved inN,N-dimethylformamide (2.5 ml), and then potassium carbonate (180 mg,1.3209 mmol), potassium iodide (15 mg) and 1H-1,2,3-triazole (0.078 ml,1.3209 mmol) were added and the mixture was heated and stirred at 60° C.for 20 minutes and then at 65° C. for 3 hours. After cooling,tetrahydrofuran and ethyl acetate were added, the mixture was washedwith saturated brine and dried over anhydrous magnesium sulfate, thesolvent was distilled off under reduced pressure, and the isomers wereseparated by silica gel column chromatography (ethyl acetate-methanolsystem). The crystals of the low polarity isomer were suspended inethanol and then washed with ethanol, filtered and dissolved indimethylsulfoxide, after which the solution was diluted with ethanol andthe precipitated crystals were filtered out, washed with ethanol andthen with diethyl ether and dried by aspiration. The crystals of thehigh polarity isomer were suspended in ethanol, washed with ethanol,filtered out, washed with ethanol and then with diethyl ether and driedby aspiration. These yielded colorless crystals of low polarityN-(4-(6-cyano-7-(2-(1,2,3-triazol-2-yl)ethoxy)-4-quinolyl)oxyphenyl)-N′-(4-fluorophenyl)urea(37 mg, 0.0703 mmol, 16.02%) and high polarityN-(4-(6-cyano-7-(2-(1,2,3-triazol-1-yl)ethoxy)-4-quinolyl)oxyphenyl)-N′-(4-fluorophenyl)urea(62 mg, 0.1182 mmol, 26.85%).

Low Polarity Isomer (Example 4-A)

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 4.81 (2H, t, J=4.6 Hz), 4.92 (2H, t,J=4.6 Hz), 6.52 (1H, d, J=5.2 Hz), 7.11 (2H, t, J=8.8 Hz), 7.22 (2H, d,J=8.8 Hz), 7.46 (2H, dd, J=5.0 Hz, 8.8 Hz), 7.59 (2H, d, J=8.8 Hz), 7.65(1H, s), 7.80 (2H, s), 8.71 (1H, s), 8.72 (1H, d, J=5.2 Hz), 8.77 (1H,s), 8.86 (1H, s).

High Polarity Isomer (Example 4-B)

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 4.72 (2H, t, J=4.8 Hz), 4.93 (2H, t,J=4.8 Hz), 6.53 (1H, d, J=5.2 Hz), 7.11 (2H, t, J=8.4 Hz), 7.23 (2H, d,J=8.8 Hz), 7.46 (2H, dd, J=4.4 Hz, 8.4 Hz), 7.59 (2H, d, J=8.8 Hz), 7.64(1H, s), 7.77 (1H, s), 8.18 (1H, s), 8.73 (1H, d, J=5.2 Hz), 8.73 (1H,s), 8.75 (1H, s), 8.83 (1H, s).

Example 5N-(4-(6-Cyano-7-(2-(1,2,3-triazol-2-yl)ethoxy)-4-quinolyl)oxyphenyl)-N′-(4-methoxyphenyl)urea(Example 5-A)N-(4-(6-Cyano-7-(2-(1,2,3-triazol-1-yl)ethoxy)-4-quinolyl)oxyphenyl)-N′-(4-methoxyphenyl)urea(Example 5-B)

TheN-(4-(6-cyano-7-(2-chloroethoxy)-4-quinolyl)oxyphenyl)-N′-(4-methoxyphenyl)urea(300 mg, 0.6136 mmol) synthesized in Example 91 was used for reaction inthe same manner as Example 4 to obtain low polarityN-(4-(6-cyano-7-(2-(1,2,3-triazol-2-yl)ethoxy)-4-quinolyl)oxyphenyl)-N′-(4-methoxyphenyl)urea(87 mg, 0.1652 mmol, 26.93%) and high polarityN-(4-(6-cyano-7-(2-(1,2,3-triazol-1-yl)ethoxy)-4-quinolyl)oxyphenyl)-N′-(4-methoxyphenyl)urea(83 mg, 0.1576 mmol, 25.69%) as colorless crystals.

Low Polarity Isomer (Example 5-A)

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.70 (3H, s), 4.81 (2H, t, J=5.0 Hz),4.92 (2H, t, J=5.0 Hz), 6.52 (1H, d, J=5.4 Hz), 6.86 (2H, d, J=8.8 Hz),7.21 (2H, d, J=9.2 Hz), 7.35 (2H, d, J=8.8 Hz), 7.57 (2H, d, J=9.2 Hz),7.65 (1H, s), 7.80 (2H, s), 8.49 (1H, s), 8.71 (1H, s), 8.72 (1H, d,J=5.4 Hz), 8.73 (1H, s).

High Polarity Isomer (Example 5-B)

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.70 (3H, s), 4.72 (2H, t, J=5.2 Hz),4.93 (2H, t, J=5.2 Hz), 6.53 (1H, d, J=5.2 Hz), 6.85 (2H, d, J=9.0 Hz),7.21 (2H, d, J=9.0 Hz), 7.35 (2H, d, J=9.0 Hz), 7.57 (2H, d, J=9.0 Hz),7.64 (1H, s), 7.77 (1H, s), 8.18 (1H, s), 8.49 (1H, s), 8.72 (1H, d,J=5.2 Hz), 8.73 (1H, s), 8.75 (1H, s).

Example 6N-(4-(6-Cyano-7-(2-(1,2,3-triazol-2-yl)ethoxy)-4-quinolyl)oxy-3-fluorophenyl)-N′-(2,4-difluorophenyl)urea(Example 6-A)N-(4-(6-Cyano-7-(2-(1,2,3-triazol-1-yl)ethoxy)-4-quinolyl)oxy-3-fluorophenyl)-N′-(2,4-difluorophenyl)urea(Example 6-B)

Sodium hydride (35 mg, 0.8774 mmol, 60% in oil) was suspended inN,N-dimethylformamide (2.5 ml), and then 1H-1,2,3-triazole (0.051 ml,0.8774 mmol) was added while cooling on ice and the mixture was stirredat room temperature for 15 minutes to complete dissolution. After thenaddingN-(4-(6-cyano-7-(2-chloroethoxy)-4-quinolyl)oxyphenyl)-N′-(2,4-difluorophenyl)urea(225 mg, 0.4386 mmol) and potassium iodide (10 mg), the mixture washeated and stirred at 50° C. for 10 hours. Upon cooling, tetrahydrofuranand ethyl acetate were added, the mixture was washed with saturatedbrine and dried over anhydrous magnesium sulfate, the solvent wasdistilled off under reduced pressure, and the isomers were separated bysilica gel column chromatography (hexane/ethyl acetate/methanol system).The crystals of the low polarity isomer were dissolved indimethylsulfoxide, the solution was diluted with ethanol, and theprecipitated crystals were filtered out, washed with ethanol and thenwith diethyl ether and dried by aspiration. The crystals of the highpolarity isomer were further purified by NH silica gel columnchromatography (hexane/ethyl acetate system), and the obtained crystalswere suspended in ethanol, washed with ethanol and hexane, and thenfiltered out, washed with hexane and dried by aspiration. This yieldedpink crystals of low polarityN-(4-(6-cyano-7-(2-(1,2,3-triazol-2-yl)ethoxy)-4-quinolyl)oxy-3-fluorophenyl)-N′-(2,4-difluorophenyl)urea(15 mg, 0.0275 mmol, 6.27%) and colorless crystals of high polarityN-(4-(6-cyano-7-(2-(1,2,3-triazol-1-yl)ethoxy)-4-quinolyl)oxy-3-fluorophenyl)-N′-(2,4-difluorophenyl)urea(30 mg, 0.0550 mmol, 12.54%).

Low Polarity Isomer (Example 6-A)

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 4.82 (2H, t, J=4.8 Hz), 4.92 (2H, t,J=4.82 Hz), 6.63 (1H, d, J=5.0 Hz), 7.05 (1H, m), 7.14 (1H, d, J=9.6Hz), 7.32 (1H, m), 7.40 (1H, m), 7.66 (1H, s), 7.80 (2H, s), 8.11 (1H,m), 8.26 (1H, t, J=9.6 Hz), 8.70 (1H, s), 8.75 (1H, d, J=5.0 Hz), 8.99(1H, s), 9.07 (1H, s).

High Polarity Isomer (Example 6-B)

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 4.73 (2H, t, J=5.2 Hz), 4.93 (2H, t,J=5.2 Hz), 6.63 (1H, d, J=5.2 Hz), 7.05 (1H, m), 7.15 (1H, m), 7.32 (1H,ddd, J=2.8 Hz, 8.8 Hz, 11.6 Hz), 7.40 (1H, dd, J=2.8 Hz, 11.6 Hz), 7.66(1H, s), 7.77 (1H, s), 8.11 (1H, m), 8.18 (1H, s), 8.26 (1H, t, J=8.8Hz), 8.74 (1H, s), 8.75 (1H, d, J=5.2 Hz), 8.99 (1H, d, J=2.2 Hz), 9.07(1H, d, J=2.2 Hz).

Example 7N-(4-(6-Cyano-7-(3-(morpholin-4-yl)propoxy)-4-quinolyl)oxyphenyl)-N′-(4-methoxyphenyl)urea

The sodium6-cyano-4-(4-((4-methoxyanilino)carbonyl)aminophenoxy)-7-quinolinolate(100 mg) synthesized in Example 87 was dissolved in dimethylformamide(2.5 ml), and then potassium carbonate (65 mg, 0.4690 mmol) and1-chloro-3-(morpholin-4-yl)propane (38 mg, 0.2345 mmol, J. Am. Chem.Soc. 67, 736 (1945)) were added and the mixture was heated and stirredat 80° C. for 2 hours. After allowing the mixture to stand and addingsaturated brine, it was extracted with ethyl acetate, the extract waswashed with saturated brine and dried over anhydrous magnesium sulfate,the solvent was distilled off under reduced pressure, and the residuewas purified by NH silica gel column chromatography (ethylacetate-methanol system). The obtained crystals were suspended in ethylacetate, the suspension was diluted with diethyl ether, and the crystalswere filtered out, washed with diethyl ether and dried by aspiration toobtain the title compound (120 mg) as light yellow crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.99 (2H, m), 2.38 (4H, brs), 2.49(2H, m), 3.57 (4H, t, J=4.6 Hz), 3.70 (3H, s), 4.33 (2H, t, J=6.2 Hz),6.51 (1H, d, J=5.6 Hz), 6.86 (2H, d, J=9.2 Hz), 7.22 (2H, d, J=9.2 Hz),7.35 (2H, d, J=9.2 Hz), 7.58 (2H, d, J=9.2 Hz), 7.59 (1H, s), 8.49 (1H,s), 8.71 (1H, d, J=5.6 Hz), 8.74 (1H, s), 8.75 (1H, s).

Example 8N-(4-(6-Cyano-7-(3-(1,2,3-triazol-2-yl)propoxy)-4-quinolyl)oxyphenyl)-N′-(4-methoxyphenyl)urea

The title compound was obtained from the sodium6-cyano-4-(4-((4-methoxyanilino)carbonyl)aminophenoxy)-7-quinolinolatesynthesized in Example 87 and 2-(3-chloropropyl)1,2,3-triazole, by thesame procedure as in Example 7.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.41 (2H, m), 3.70 (3H, s), 4.29 (2H,t, J=6.0 Hz), 4.68 (2H, t, J=6.6 Hz), 6.52 (1H, d, J=5.2 Hz), 6.86 (2H,d, J=8.8 Hz), 7.22 (2H, d, J=8.8 Hz), 7.35 (2H, d, J=8.8 Hz), 7.54 (1H,s), 7.58 (2H, d, J=8.8 Hz), 7.78 (2H, s), 8.49 (1H, s), 8.71 (1H, d,J=5.2 Hz), 8.74 (1H, s), 8.77 (1H, s).

Example 9N-(4-(6-Cyano-7-(3-(1,2,3-triazol-1-yl)propoxy)-4-quinolyl)oxyphenyl)-N′-(4-methoxyphenyl)urea

The title compound was obtained from the sodium6-cyano-4-(4-((4-methoxyanilino)carbonyl)aminophenoxy)-7-quinolinolatesynthesized in Example 87 and 1-(3-chloropropyl)-1,2,3-triazole, by thesame procedure as in Example 7.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.41 (2H, m), 3.70 (3H, s), 4.28 (2H,t, J=6.0 Hz), 4.63 (2H, t, J=6.6 Hz), 6.52 (1H, d, J=5.4 Hz), 6.86 (2H,d, J=8.8 Hz), 7.22 (2H, d, J=8.8 Hz), 7.35 (2H, d, J=8.8 Hz), 7.57 (1H,s), 7.58 (2H, d, J=8.8 Hz), 7.73 (1H, s), 8.19 (1H, s), 8.49 (1H, s),8.72 (1H, d, J=5.4 Hz), 8.74 (1H, s), 8.77 (1H, s).

Example 10N-(4-(6-Cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)-N′-(4-fluorophenyl)urea

4-(4-Aminophenoxy)-7-(2-methoxyethoxy)-6-cyanoquinoline (109 mg, 0.325mmol) was dissolved in toluene (5 ml) while heating, and then4-fluorophenyl isocyanate (0.057 ml, 0.488 mmol) was added and themixture was heated to reflux for 1 hour. After cooling, the precipitatedcrystals were filtered out, washed with ethyl acetate and dried underreduced pressure to obtain the title compound (148 mg, 0.311 mmol,96.4%) as white crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.36 (3H, s), 3.76-3.79 (2H, m),4.41-4.43 (2H, m), 6.52 (1H, d, J=5.2 Hz), 7.11 (2H, t, J=9.0 Hz), 7.23(2H, d, J=9.0 Hz), 7.46 (2H, q, J=4.8 Hz), 7.57-7.62 (3H, m), 8.71-8.76(3H, m), 8.82 (1H, s).

Example 11N-(4-(6-Cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)-N′-(2-pyridyl)urea

Phenyl N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)carbamate(104 mg, 0.228 mmol) was dissolved in dimethylsulfoxide (1 ml), and then2-aminopyridine (43 mg, 0.457 mmol) was added and the mixture was heatedat 85° C. for 3 hours while stirring. After cooling, ethyl acetate andwater were added for distribution, and the organic layer was washed withsaturated brine and dried over anhydrous sodium sulfate. After filteringoff the drying agent and concentrating under reduced pressure, ethylacetate-hexane was added to the residue and the precipitated crystalswere filtered out and dried under reduced pressure to obtain the titlecompound (86 mg, 0.189 mmol, 82.7%) as white crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.36 (3H, s), 3.75-3.78 (2H, m),4.39-4.42 (2H, m), 6.53 (1H, d, J=5.2 Hz), 6.99 (1H, m), 7.18 (1H, d,J=8.4 Hz), 7.26 (2H, d, J=9.2 Hz), 7.56 (1H, d, J=8.4 Hz), 7.62 (1H, s),7.68-7.77 (3H, m), 8.26 (1H, d, J=5.2 Hz), 8.72 (1H, d, J=5.2 Hz), 8.77(1H, s), 9.89 (1H, brs).

Example 12N-(4-(6-Cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)-N′-(1,3-thiazol-2-yl)urea

The title compound (37 mg, 0.08 mmol, 34.4%) was obtained as light browncrystals from phenylN-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)carbamate (106mg, 0.233 mmol) by the same procedure as in Example 11.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.36 (3H, s), 3.75-3.79 (2H, m),4.40-4.43 (2H, m), 6.53 (1H, d, J=5.6 Hz), 7.10 (1H, d, J=3.2 Hz), 7.72(1H, d, J=8.8 Hz), 7.37 (1H, m), 7.57-7.67 (3H, m), 8.72 (1H, d, J=5.2Hz), 8.77 (1H, s), 9.53 (1H, brs).

Example 13N-(4-(6-Cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)-N′-(4-hydroxyphenyl)urea

The title compound (52 mg, 0.110 mmol, 43.0%) was obtained as lightbrown crystals from phenylN-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)carbamate (117mg, 0.257 mmol) by the same procedure as in Example 11.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.36 (3H, s), 3.77-3.79 (2H, m),4.41-4.43 (2H, m), 6.51 (1H, d, J=5.2 Hz), 6.67 (2H, d, J=8.0 Hz),7.15-7.25 (3H, m), 7.57 (2H, d, J=8.0 Hz), 7.62 (1H, s), 8.37 (1H, s),8.70-8.76 (3H, m), 9.05 (1H, s).

Example 14N-(4-(6-Cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)-N′-(3-methoxyphenyl)urea

The title compound (50 mg, 0.103 mmol, 39.2%) was obtained as whitecrystals from phenylN-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)carbamate (120mg, 0.263 mmol) by the same procedure as in Example 11.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.36 (3H, s), 3.72 (3H, s), 3.76-3.79(2H, m), 4.39-4.43 (2H, m), 6.50-6.57 (2H, m), 6.93 (1H, d, J=8.0 Hz),7.14-7.19 (2H, m), 7.24 (2H, d, J=8.8 Hz), 7.59 (2H, d, J=8.8 Hz), 7.62(1H, s), 8.69-8.73 (2H, m), 8.76 (1H, s), 8.80 (1H, s).

Example 15N-(4-(6-Cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)-N′-(3-hydroxyphenyl)urea

The title compound (25 mg, 0.053 mmol, 23.7%) was obtained as lightbrown crystals from phenylN-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)carbamate (102mg, 0.234 mmol) by the same procedure as in Example 11.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.36 (3H, s), 3.75-3.79 (2H, m),4.40-4.43 (2H, m), 6.36 (1H, d, J=9.2 Hz), 6.52 (1H, d, J=5.2 Hz), 6.79(1H, d, J=8.0 Hz), 7.00-7.06 (2H, m), 7.23 (2H, d, J=9.2 Hz), 7.58 (2H,d, J=8.8 Hz), 7.62 (1H, s), 8.59 (1H, s), 8.71 (1H, d, J=4.8 Hz), 8.76(1H, s), 9.31 (1H, brs).

Example 16N-(4-(6-Cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)-N′-(2-hydroxyphenyl)urea

The title compound (78 mg, 0.166 mmol, 69.9%) was obtained as lightbrown crystals from phenylN-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)carbamate (108mg, 0.237 mmol) by the same procedure as in Example 11.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.36 (3H, s), 3.76-3.79 (2H, m),4.40-4.43 (2H, m), 6.52 (1H, d, J=5.6 Hz), 6.69-6.85 (3H, m), 7.22 (2H,d, J=8.8 Hz), 7.57-7.62 (3H, m), 7.99 (1H, d, J=8.0 Hz), 8.34 (1H, br),8.71 (1H, d, J=5.2 Hz), 8.76 (1H, s), 9.62 (1H, brs).

Example 17N-(4-(6-Cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)-N′-(1H-2-imidazolyl)urea

After dissolving 2-aminoimidazole (132 mg, 1.0 mmol) in adimethylformamide (2 ml) and water (1 ml) mixed solvent, triethylamine(0.42 ml, 3.0 mmol) and phenyl chloroformate (0.14 ml, 1.1 mmol) wereadded at room temperature, and the mixture was stirred for 10 minutes.After further adding4-(4-aminophenoxy)-7-(2-methoxyethoxy)-6-cyanoquinoline (168 mg, 0.5mmol), the mixture was stirred overnight. The reaction solution wasdiluted with ethyl acetate (30 ml) and then washed with water (10 ml×2)and saturated brine (10 ml), and the organic layer was dried overanhydrous sodium sulfate. The drying agent was filtered off, thefiltrate was concentrated under reduced pressure, and the residue waspurified by silica gel column chromatography (eluent—ethylacetate:ethanol=95:5) to obtain the title compound (20 mg, 0.045 mmol,8.98%) as white crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.36 (3H, s), 3.76-3.79 (2H, m),4.40-4.43 (2H, m), 6.53 (1H, d, J=5.2 Hz), 6.70 (1H, s), 7.24 (2H, d,J=8.8 Hz), 7.57-7.67 (3H, m), 8.72 (1H, d, J=5.6 Hz), 8.76 (1H, s).

Example 18N-(4-(6-Cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)-N′-(2,4-difluorophenyl)urea

The title compound (136 mg, 0.277 mmol, 87.7%) was obtained as whitecrystals from 4-(4-aminophenoxy)-7-(2-methoxyethoxy)-6-cyanoquinoline(106 mg, 0.316 mmol) by the same procedure as in Example 10.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.36 (3H, s), 3.76-3.79 (2H, m),4.40-4.43 (2H, m), 6.52 (1H, d, J=5.2 Hz), 7.04 (1H, m), 7.23-7.34 (3H,m), 7.57-7.62 (3H, m), 8.06 (1H, m), 8.52 (1H, s), 8.71 (1H, d, J=5.6Hz), 8.76 (1H, s), 9.16 (1H, s).

Example 19N-(4-(6-Cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)-N′-(3-cyanophenyl)urea

The title compound (38 mg, 0.079 mmol, 33.1%) was obtained as lightyellow crystals from phenylN-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)carbamate (109mg, 0.239 mmol) by the same procedure as in Example 11.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.36 (3H, s), 3.76-3.79 (2H, m),4.40-4.43 (2H, m), 6.52 (1H, d, J=5.2 Hz), 7.26 (2H, d, J=8.8 Hz), 7.41(1H, d, J=6.4 Hz), 7.49 (1H, t, J=8.0 Hz), 7.55-7.62 (3H, m), 7.68 (1H,dd, J=1.2, 8.8 Hz), 7.97 (1H, s), 8.71 (1H, d, J=6.4 Hz), 8.76 (1H, s),9.00 (1H, s), 9.05 (1H, s).

Example 20N-(4-(6-Cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)-N′-(2-fluorophenyl)urea

The title compound (75 mg, 0.159 mmol, 48.8%) was obtained as whitecrystals from 4-(4-aminophenoxy)-7-(2-methoxyethoxy)-6-cyanoquinoline(109 mg, 0.325 mmol) by the same procedure as in Example 10.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.36 (3H, s), 3.76-3.79 (2H, m),4.40-4.43 (2H, m), 6.52 (1H, d, J=5.2 Hz), 7.01 (1H, m), 7.13 (1H, t,J=8.0 Hz), 7.20-7.27 (3H, m), 7.55-7.63 (3H, m), 8.14 (1H, t, J=8.0 Hz),8.56 (1H, brs), 8.72 (1H, d, J=6.4 Hz), 8.76 (1H, s), 9.22 (1H, s).

Example 21N-(4-(6-Cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)-N′-(3-(methylsulfonyl)phenyl)urea

Diisopropylethylamine (0.057 ml, 0.328 mmol) andphenylN-[3-(methylsulfonyl)phenyl]carbamate (96 mg, 0.328 mmol) werereacted with 4-(4-aminophenoxy)-7-(2-methoxyethoxy)-6-cyanoquinoline(100 mg, 0.298 mmol), and the title compound (120 mg, 0.225 mmol, 75.6%)was obtained as white crystals by the same procedure as in Example 34.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.19 (3H, s), 3.36 (3H, s), 3.76-3.79(2H, m), 4.40-4.43 (2H, m), 6.53 (1H, d, J=5.6 Hz), 7.26 (2H, d, J=8.8Hz), 7.50-7.69 (6H, m), 8.16 (1H, brs), 8.72 (1H, d, J=5.2 Hz), 8.76(1H, s), 8.95 (1H, s), 9.15 (1H, s).

Example 22N-(4-(6-Cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)-N′-(3-(methylsulfanyl)phenyl)urea

The title compound (210 mg, 0.420 mmol, 98.9%) was obtained as whitecrystals from phenylN-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)carbamate (193mg, 0.424 mmol) by the same procedure as in Example 11.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.43 (3H, s), 3.36 (3H, s), 3.76-3.79(2H, m), 4.40-4.43 (2H, m), 6.52 (1H, d, J=5.2 Hz), 6.83 (1H, d, J=7.2Hz), 7.14-7.24 (4H, m), 7.48 (1H, s), 7.58-7.61 (3H, m), 8.71 (1H, d,J=5.2 Hz), 8.75 (1H, s), 9.62 (1H, s), 9.76 (1H, s).

Example 23N-(4-(6-Cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)-N′-cyclopropylurea

The title compound (145 mg, 0.347 mmol, 80.9%) was obtained as whitecrystals from phenylN-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)carbamate (195mg, 0.428 mmol) by the same procedure as in Example 11.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.4 (2H, brs), 0.63 (2H, d, J=6.8Hz), 2.53 (1H, m), 3.36 (3H, s), 3.76-3.79 (2H, m), 4.40-4.43 (2H, m),6.42 (1H, s), 6.48 (1H, d, J=5.2 Hz), 6.97 (2H, d, J=9.2 Hz), 7.53 (2H,d, J=9.2 Hz), 7.60 (1H, s), 8.44 (1H, s), 8.70 (1H, d, J=4.8 Hz), 8.74(1H, s).

Example 24N-(4-(6-Cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)-N′-(4-fluoro-2-hydroxyphenyl)urea

The title compound (132 mg, 0.270 mmol, 78.9%) was obtained as lightyellow crystals from phenylN-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)carbamate (156mg, 0.343 mmol) by the same procedure as in Example 11.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.36 (3H, s), 3.76-3.79 (2H, m),4.40-4.43 (2H, m), 6.52 (1H, d, J=5.6 Hz), 6.57 (1H, m), 6.62 (1H, m),7.23 (2H, d, J=8.8 Hz), 7.57 (2H, d, J=8.8 Hz), 7.62 (1H, s), 7.98 (1H,m), 8.12 (1H, s), 8.71 (1H, d, J=5.6 Hz), 9.40 (1H, s), 10.47 (1H, s).

Example 25N-(4-(6-Cyano-7-(2-methoxyethoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-(1,3-thiazol-2-yl)urea

Phenyl N-(4(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxy-2-fluorophenyl)carbamate(200 mg) and 2-aminothiazole (85 mg) were dissolved in 1 ml ofdimethylformamide, and then 0.12 ml of triethylamine was added theretoand the mixture was heated and stirred at 90° C. for 2 hours. Aftercooling, water was added and the precipitated solid was filtered out andwashed with ethyl acetate to obtain 110 mg of the title compound aslight brown crystals (57% yield).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.37 (3H, s), 3.75-3.80 (2H, m),4.40-4.45 (2H, m), 6.63 (1H, d, J=5.6 Hz), 7.14 (1H, d, J=3.2 Hz),7.16-7.20 (1H, m), 7.39 (1H, d, J=3.2 Hz), 7.42-7.47 (1H, m), 7.64 (1H,s), 8.21-8.27 (1H, m), 8.74-8.76 (2H, m)

Example 26N-(4-(6-Cyano-7-(2-methoxyethoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-cyclopropylurea

The title compound (83 mg, 0.190 mmol, 61.3%) was obtained as whitecrystals from phenylN-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxy-2-fluorophenyl)carbamate(147 mg, 0.310 mmol) by the same procedure as in Example 25.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.40 (2H, br), 0.61-0.66 (2H, m),2.53 (1H, m), 3.36 (3H, s), 3.76-3.79 (2H, m), 4.40-4.43 (2H, m), 6.58(1H, d, J=5.6 Hz), 6.79 (1H, d, J=2.0 Hz), 7.08 (1H, dd, J=2.0, 10.4Hz), 7.32 (1H, dd, J=2.4, 11.6 Hz), 7.62 (1H, s), 8.18-8.22 (2H, m),8.71-8.74 (2H, m).

Example 27N-(4-(6-Cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)-N′-cyclopropylmethylurea

The title compound (144 mg, 0.333 mmol, 96.6%) was obtained as whitecrystals from phenylN-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)carbamate (157mg, 0.345 mmol) by the same procedure as in Example 11.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.16-0.18 (2H, m), 0.39-0.43 (2H, m),0.94 (1H, m), 2.97 (2H, t, J=6.4 Hz), 3.36 (3H, s), 3.76-3.79 (2H, m),4.40-4.43 (2H, m), 6.22 (1H, m), 6.49 (1H, d, J=5.6 Hz), 7.17 (2H, d,J=8.8 Hz), 7.52 (2H, d, J=8.8 Hz), 7.61 (1H, s), 8.60 (1H, s), 8.70 (1H,d, J=5.2 Hz), 8.75 (1H, s).

Example 28N-(4-(6-Cyano-7-(2-methoxyethoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-cyclopropylmethylurea

The title compound (83 mg, 0.190 mmol, 61.3%) was obtained as whitecrystals from phenylN-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxy-2-fluorophenyl)carbamate(147 mg, 0.310 mmol) by the same procedure as in Example 25.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.16-0.18 (2H, m), 0.41-0.46 (2H, m),0.94 (1H, m), 2.99 (2H, t, J=6.0 Hz), 3.36 (3H, s), 3.76-3.79 (2H, m),4.40-4.43 (2H, m), 6.58 (1H, d, J=5.6 Hz), 6.71 (1H, t, J=5.6 Hz), 7.08(1H, d, J=9.2 Hz), 7.33 (1H, dd, J=2.8, 11.6 Hz), 7.63 (1H, s), 8.24(1H, t, J=9.2 Hz), 8.38 (1H, s), 8.55-8.59 (2H, m).

Example 29N-(4-(6-Cyano-7-(3-(morpholin-4-yl)propoxy)-4-quinolyloxy)-2-fluorophenyl)-N′-(2,4-difluorophenyl)urea

N-(4-(6-Cyano-7-hydroxyquinolin-4-yloxy)-2-fluorophenyl)-N-(2,4-difluorophenyl)urea(100 mg, 0.2220 mmol) was used for reaction in the same manner asExample 7 to obtain the title compound (35 mg, 0.0606 mmol, 27.30%) aslight yellow crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.99 (2H, m), 2.38 (4H, brs), 2.50(2H, t, J=7.2 Hz), 3.57 (4H, t, J=4.6 Hz), 4.33 (2H, t, J=6.4 Hz), 6.62(1H, d, J=5.4 Hz), 7.06 (1H, m), 7.15 (1H, m), 7.32 (1H, ddd, J=2.8 Hz,8.8 Hz, 11.6 Hz), 7.41 (1H, dd, J=2.8 Hz, 11.6 Hz), 7.61 (1H, s), 8.12(1H, m), 8.27 (1H, dt, J=2.0 Hz, 9.2 Hz), 8.74 (1H, s), 8.74 (1H, d,J=5.4 Hz), 8.99 (1H, m), 9.07 (1H, m).

Example 30N-(4-(6-Cyano-7-(3-(diethylamino)propoxy)-4-quinolyloxyphenyl)-N′-(4-fluorophenyl)urea

The title compound (69 mg, 0.131 mmol, 51.9%) was obtained as lightbrown crystals from sodium6-cyano-4-(4-((4-fluoroanilino)carbonyl)aminophenoxy)-7-quinolinolate(110 mg, 0.252 mmol) by the same procedure as in Example 7.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.95 (6H, t, J=7.2 Hz), 1.89-1.95(2H, m), 2.44-2.49 (4H, m), 2.58-2.62 (2H, m), 4.31 (2H, t, J=6.0 Hz),6.51 (1H, d, J=5.2 Hz), 7.11 (2H, t, J=8.4 Hz), 7.23 (2H, d, J=8.8 Hz),7.44-7.48 (2H, m), 7.56-7.57 (2H, m), 7.60 (1H, s), 8.71 (1H, d, J=5.2Hz), 8.74-8.76 (2H, m), 8.85 (1H, s).

Example 31N-(4-(6-Cyano-7-(3-(4-morpholino)propyl)-4-quinolyl)oxyphenyl)-N′-(4-fluorophenyl)urea

The title compound (73 mg, 0.135 mmol, 53.5%) was obtained as lightbrown crystals from sodium6-cyano-4-(4-((4-fluoroanilino)carbonyl)aminophenoxy)-7-quinolinolate(110 mg, 0.252 mmol) by the same procedure as in Example 7.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.99 (2H, t, J=6.4 Hz), 2.30-2.60(6H, m), 3.55-3.58 (4H, m), 4.31-4.34 (2H, m), 6.51 (1H, d, J=5.2 Hz),7.11 (2H, t, J=8.8 Hz), 7.23 (2H, d, J=9.2 Hz), 7.44-7.48 (2H, m),7.57-7.60 (3H, m), 8.70-8.75 (3H, m), 8.82 (1H, s).

Example 32N-(4-(6-Cyano-7-(2-methoxyethoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-(2-pyridyl)urea

The title compound (210 mg, 84% yield) was obtained as light browncrystals from phenylN-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxy-2-fluorophenyl)carbamate(250 mg) and 2-aminopyridine (100 mg), in the same manner as Example 25.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.36 (3H, s), 3.75-3.80 (2H, m),4.39-4.45 (2H, m), 6.64 (1H, d, J=5.2 Hz), 7.00-7.05 (1H, m), 7.15-7.19(1H, m), 7.37-7.47 (2H, m), 7.64 (1H, s), 7.50-7.80 (1H, m), 8.25-8.30(1H, m), 8.31-8.37 (1H, m), 8.74 (1H, d, J=5.2 Hz), 8.76 (1H, s), 9.87(1H, s)

Example 33N-(4-(6-Cyano-7-(2-methoxyethoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-(3-(methylsulfanyl)phenyl)urea

The title compound (100 mg, 61% yield) was obtained as light browncrystals from phenylN-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxy-2-fluorophenyl)carbamate(160 mg) and 3-(methylthio)aniline (88 mg), in the same manner asExample 25.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.43 (3H, s), 3.36 (3H, s), 3.75-3.80(2H, m), 4.40-4.45 (2H, m), 6.62 (1H, d, J=5.6 Hz), 6.86-6.89 (1H, m),7.11-7.17 (2H, m), 7.20-7.25 (1H, m), 7.37-7.43 (1H, m), 7.47 (1H, s),7.63 (1H, s), 8.21-8.28 (1H, m), 8.66 (1H, brs), 8.73-8.76 (2H, m),9.11-9.13 (1H, m)

Example 34N-(4-(6-Cyano-7-(2-methoxyethoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-(3-(methylsulfonyl)phenyl)urea

4-(4-Amino-3-fluorophenoxy)-6-cyano-7-(2-methoxyethoxy)quinoline (106mg) and phenyl

N-(3-(methylsulfonyl)phenyl)carbamate (96 mg) were added to 5 ml oftoluene, and then 0.06 ml of diisopropylethylamine was added and themixture was heated to reflux for 3 hours. After cooling, ethyl acetatewas added and the precipitated insoluble portion was filtered out. Thefiltrate was concentrated, the resulting residue was dissolved intetrahydrofuran, toluene was added, and the precipitated solid wasfiltered out to obtain 13 mg of the title compound as light browncrystals (8% yield).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.20 (3H, s), 3.35 (3H, s), 3.75-3.80(2H, m), 4.38-4.43 (2H, m), 6.63 (1H, d, J=5.2 Hz), 7.14-7.17 (1H, m),7.39-7.45 (1H, m), 7.51-7.61 (2H, m) 7.62-7.70 (2H, m), 8.16-8.27 (2H,m), 8.73-8.76 (3H, m), 9.47-9.49 (1H, m)

Example 35N-(4-(6-Cyano-7-(2-methoxyethoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-(2-fluorophenyl)urea

4-(4-Amino-3-fluorophenoxy)-6-cyano-7-(2-methoxyethoxy)quinoline (100mg) was added to 4.5 ml of toluene, and the mixture was heated toreflux. After then adding 2-fluorophenylisocyanate (0.05 ml), themixture was further heated to reflux for 1 hour. After cooling, theprecipitated solid was filtered out and washed with ethylacetate/toluene=1/1 to obtain 100 mg of the title compound as lightbrown crystals (72% yield).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.37 (3H, s), 3.75-3.80 (2H, m),4.40-4.45 (2H, m), 6.62 (1H, d, J=5.6 Hz), 6.97-7.05 (1H, m), 7.11-7.18(1H, m), 7.21-7.28 (1H, m), 7.38-7.45 (1H, m), 7.64 (1H, s), 8.14-8.20(1H, m), 8.26-8.33 (1H, m), 8.73-8.76 (2H, m), 9.06 (1H, brs), 9.14 (1H,brs)

Example 36N-(4-(6-Cyano-7-methoxy-4-quinolyl)oxyphenyl)-N′-(2,4-difluorophenyl)urea

4-(4-Aminophenoxy)-6-cyano-7-methoxyquinoline (180 mg) was added to 5.5ml of toluene, and the mixture was heated to reflux. After then adding2,4-difluorophenyl isocyanate (0.12 ml), the mixture was further heatedto reflux for 1 hour. After cooling, the precipitated solid was filteredout and washed with ethyl acetate/toluene=1/1 to obtain 195 mg of thetitle compound as light brown crystals (70% yield).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 4.05 (3H, s), 6.52 (1H, d, J=5.2 Hz),7.01-7.08 (1H, m), 7.21-7.34 (3H, m), 7.56-7.62 (3H, m), 8.02-8.10 (1H,m), 8.52 (1H, s), 8.72 (1H, d, J=5.2 Hz), 8.76 (1H, s), 9.18 (1H, s).

Example 37 N-(4-(6-Cyano-7-methoxy-4-quinolyl)oxyphenyl)-N′-phenylurea

4-(4-Aminophenoxy)-6-cyano-7-methoxyquinoline (148 mg) was added to 5.5ml of toluene, and the mixture was heated to reflux. After then addingphenyl isocyanate (0.08 ml), the mixture was further heated to refluxfor 1 hour. After cooling, the precipitated solid was filtered out andwashed with ethyl acetate/toluene=1/1 to obtain 150 mg of the titlecompound as light brown crystals. ¹H-NMR Spectrum (DMSO-d₆) δ (ppm):4.05 (3H, s), 6.50-6.54 (1H, m), 6.96 (t, 1H, 7.2 Hz), 7.23 (2H, d,J=9.2 Hz), 7.27 (2H, d, J=7.2 Hz), 7.44 (2H, d, J=7.2 Hz), 7.56-7.62(3H, m), 8.68-8.77 (3H, m), 8.83 (1H, brs).

Example 38N-(4-(6-Cyano-7-methoxy-4-quinolyl)oxyphenyl)-N′-(1-butyl)urea

4-(4-Aminophenoxy)-6-cyano-7-methoxyquinoline (150 mg) was added to 2.5ml of toluene and 2.5 ml of acetonitrile, and the mixture was heated toreflux. After then adding n-butyl isocyanate (0.12 ml), the mixture wasfurther heated to reflux for 1 hour. After cooling, the precipitatedsolid was filtered out and washed with ethyl acetate/toluene=1/1 toobtain 110 mg of the title compound as light brown crystals (55% yield).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.88 (3H, t, J=7.6 Hz), 1.25-1.45(4H, m), 3.04-3.11 (2H, m), 4.05 (3H, s), 6.13 (1H, t, J=5.6 Hz), 6.49(1H, d, J=5.6 Hz), 7.16 (2H, d, J=9.2 Hz), 7.52 (2H, d, J=9.2 Hz), 7.58(1H, s), 8.55 (1H, s), 8.71 (1H, d, J=5.6 Hz), 8.75 (1H, s)

Example 39N-(4-(6-Cyano-7-methoxy-4-quinolyl)oxyphenyl)-N′-(4-fluorophenyl)urea

4-(4-Aminophenoxy)-6-cyano-7-methoxyethoxyquinoline (150 mg) was addedto 5.0 ml of toluene and 2.5 ml of acetonitrile, and the mixture washeated to reflux. After then adding 4-fluorophenyl isocyanate (0.12 ml),the mixture was further heated to reflux for 1 hour. After cooling, theprecipitated solid was filtered out and washed with ethylacetate/toluene=1/1 to obtain 150 mg of the title compound as lightbrown crystals (68% yield).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 4.05 (3H, s), 6.52 (1H, d, J=5.6 Hz),7.08-7.14 (2H, m), 7.23 (2H, d, J=8.8 Hz), 7.43-7.49 (2H, m), 7.56-7.61(3H, m), 8.71-8.76 (3H, m), 8.85 (1H, s)

Example 40N-(4-(6-Cyano-7-methoxy-4-quinolyl)oxyphenyl)-N′-(2-pyridyl)urea

Phenyl N-(4-(6-cyano-7-methoxy-4-quinolyl)oxyphenyl)carbamate (150 mg)and 2-aminopyridine (69 mg) were dissolved in 1 ml of dimethylsulfoxide,and the solution was heated and stirred at 80° C. for 1.5 hours. Aftercooling, water was added, and the precipitated solid was filtered outand washed with ethyl acetate to obtain 82 mg of the title compound aslight brown crystals (54% yield).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 4.05 (3H, s), 6.54 (1H, d, J=5.6 Hz),6.98-7.03 (1H, m), 7.26-7.30 (2H, m), 7.45-7.52 (1H, m), 7.60 (1H, s),7.63-7.78 (3H, m), 8.25-8.30 (1H, m), 8.73 (1H, d, J=5.6 Hz), 8.78 (1H,s), 9.59 (1H, s), 10.67 (1H, s)

Example 41N-(4-(6-Cyano-7-methoxyethoxy-4-quinolyl)oxyphenyl)-N′-(3-pyridyl)urea

The title compound (32 mg, 32% yield) was obtained as light browncrystals from phenylN-(4-(6-cyano-7-methoxy-4-quinolyl)oxyphenyl)carbamate (100 mg) and3-aminopyridine (46 mg), in the same manner as Example 40.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 4.05 (3H, s), 6.53 (1H, d, J=5.2 Hz),7.22-7.34 (3H, m), 7.57-7.63 (3H, m), 7.91-7.96 (1H, m), 8.17-8.20 (1H,m), 8.59-8.63 (1H, m), 8.73 (1H, d, J=5.2 Hz), 8.76 (1H, s), 8.91 (1H,brs), 9.00 (1H, brs).

Example 42N-(4-(6-Cyano-7-methoxyethoxy-4-quinolyl)oxyphenyl)-N′-(4-pyridyl)urea

The title compound (45 mg, 30% yield) was obtained as light browncrystals from phenylN-(4-(6-cyano-7-methoxy-4-quinolyl)oxyphenyl)carbamate (150 mg) and4-aminopyridine (69 mg), in the same manner as Example 40.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 4.05 (3H, s), 6.54 (1H, d, J=5.2 Hz),7.26 (2H, d, J=9.0 Hz), 7.43 (2H, d, J=7.0 Hz), 7.57-7.64 (3H, m), 8.35(2H, d, J=7.0 Hz), 8.71-8.77 (2H, m), 9.05 (1H, brs), 9.16 (1H, brs).

Example 43N-(4-(6-Cyano-7-(3-(diethylamino)propoxy)-4-quinolyl)oxyphenyl)-N′-(4-methoxyphenyl)urea

The title compound (10 mg) was obtained from sodium6-cyano-4-(4-((4-methoxyanilino)carbonyl)aminophenoxy)-7-quinolinolate(131 mg) by the same procedure as in Example 7.

¹H-NMR(CDCl₃) δ (ppm): 2.02-2.15 (2H, m), 2.27 (6H, s), 2.54 (2H, t,J=7.4 Hz), 3.80 (3H, s), 4.28 (2H, t, J=7.4 Hz), 6.42 (1H, d, J=5.3 Hz),6.80 (1H, brs), 6.90 (2H, d, J=9.3 Hz), 7.03 (1H, brs), 7.08 (2H, d,J=9.3 Hz), 7.28 (2H, d, J=9.3 Hz), 7.46 (1H, s), 7.48 (2H, d, J=9.3 HZ),8.62 (1H, d, J=5.3 Hz), 8.66 (1H, s)

Example 44N-[4-(6-Cyano-7-(2-(dimethylamino)ethoxy)-4-quinolyl)oxyphenyl)-N′-(4-methoxyphenyl)urea

The title compound (110 mg) was obtained from sodium6-cyano-4-(4-((4-methoxyanilino)carbonyl)aminophenoxy)-7-quinolinolate(145 mg), by the same procedure as in Example 7.

¹H-NMR (DMSO-d₆) δ (ppm): 2.28 (6H, s), 2.76 (2H, t, J=5.3 Hz), 3.70(3H, s), 4.37 (2H, t, J=5.3 Hz), 6.51 (1H, d, J=5.4 Hz), 6.86 (2H, d,J=8.7 Hz), 7.21 (2H, d, J=8.7 Hz), 7.35 (2H, d, J=8.7 Hz), 7.58 (2H, d,J=8.7 Hz), 7.62 (1H, s), 8.50 (1H, s), 8.72 (1H, d, J=5.4 Hz), 8.75 (2H,s)

Example 45N-(4-(6-Cyano-7-(3-(1-pyrrolidino)propoxy)-4-quinolyl)oxyphenyl-N′-(4-methoxyphenyl)urea

N-(4-(6-Cyano-7-(3-chloropropoxy)-4-quinolyl)oxyphenyl)-N′-(4-methoxyphenyl)urea(140 mg) was dissolved in dimethylformamide, pyrrolidine (163 μl) wasadded, and the mixture was heated and stirred at 80° C. for 6 hours. Thereaction solution was poured into saturated brine and extracted withethyl acetate. The organic layer was dried over magnesium sulfate andconcentrated. The residue was passed through NH silica gel (Fuji SilysiaChemical) and eluted with a solvent (ethyl acetate), and then furthereluted with another solvent (ethyl acetate:methanol=10:1) andconcentrated to obtain 31 mg of the title compound.

¹H-NMR (DMSO-d₆) δ (ppm): 1.67-1.73 (4H, m), 1.96-2.04 (2H, m),2.44-2.49 (4H, m), 2.61 (2H, t, J=6.8 Hz), 3.72 (3H, s), 4.34 (2H, t,J=6.4 Hz), 6.53 (1H, d, J=5.2 Hz), 6.88 (2H, d, J=8.8 Hz), 7.23 (2H, d,J=9.2 Hz), 7.37 (2H, d, J=8.8 Hz), 7.60 (1H, s), 7.61 (2H, d, J=9.2 Hz),8.63 (1H, brs), 8.73 (1H, d, J=5.2 HZ), 8.76 (1H, s), 8.88 (1H, brs).

Example 46N-(4-(6-Cyano-7-(3-(1-piperidino)propoxy)-4-quinolyl)oxyphenyl)-N′-(4-methoxyphenyl)urea

The title compound (67 mg) was obtained from sodium6-cyano-4-(4-((4-methoxyanilino)carbonyl)aminophenoxy)-7-quinolinolate(156 mg), by the same procedure as in Example 7.

¹H-NMR (DMSO-d₆) δ (ppm): 1.30-1.57 (6H, m), 1.93-2.03 (2H, m),2.31-2.53 (6H, m), 3.72 (3H, s), 4.33 (2H, t, J=6.5 Hz), 6.52 (1H, d,J=4.9 Hz), 6.87 (2H, d, J=8.9 Hz), 7.23 (2H, d, J=8.9 Hz), 7.38 (2H, d,J=8.9 Hz), 7.57-7.63 (3H, m), 8.53 (1H, brs), 8.72 (1H, d, J=4.9 Hz),8.76 (1H, s), 8.79 (1H, brs)

Example 47N-(4-(6-Cyano-7-(2-(1-pyrrolidino)ethoxy)-4-quinolyl)oxyphenyl)-N′-(4-methoxyphenyl)urea

The title compound (54 mg) was obtained from sodium6-cyano-4-(4-((4-methoxyanilino)carbonyl)aminophenoxy)-7-quinolinolate(188 mg), by the same procedure as in Example 7.

¹H-NMR (DMSO-d₆) δ (ppm): 1.68-1.74 (4H, m), 2.58-2.65 (4H, m), 2.93(2H, t, J=6.4 Hz), 3.72 (3H, s), 4.40 (2H, t, J=6.4 Hz), 6.53 (1H, d,J=5.7 Hz), 6.88 (2H, d, J=9.1 Hz), 7.24 (2H, d, J=9.1 Hz), 7.37 (2H, d,J=9.1 Hz), 7.60 (2H, d, J=9.1 Hz), 7.62 (1H, s), 8.52 (1H, s), 8.73 (1H,d, J=5.7 Hz), 8.77 (2H, s)

Example 48N-(4-(6-Cyano-7-(3-(diethylamino)propoxy)-4-quinolyl)oxyphenyl)-N′-(4-methoxyphenyl)urea

The title compound (45 mg) was obtained from sodium6-cyano-4-(4-((4-methoxyanilino)carbonyl)aminophenoxy)-7-quinolinolate(134 mg), by the same procedure as in Example 7.

¹H-NMR (DMSO-d₆) δ (ppm): 0.97 (6H, t, J=7.8 Hz), 1.88-1.96 (2H, m),2.43-2.53 (4H, m), 2.61 (2H, t, J=7.8 Hz), 3.72 (3H, s), 4.33 (2H, t,J=7.8 Hz), 6.53 (1H, d, J=5.2 Hz), 6.88 (2H, d, J=8.8 Hz), 7.24 (2H, d,J=8.8 Hz), 7.38 (2H, d, J=8.8 Hz), 7.53-7.63 (3H, m), 8.55 (1H, s), 8.73(1H, d, J=5.2 Hz), 8.76 (1H, s), 8.80 (1H, s)

Example 49N-(4-(6-Cyano-7-(3-(dimethylamino)propoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-(2,4-difluorophenyl)urea

The title compound (35 mg) was obtained from sodium6-cyano-4-(4-((2,4-difluoroanilino)carbonyl)amino-3-fluorophenoxy)-7-quinolinolate(100 mg), by the same procedure as in Example 7.

¹H-NMR (DMSO-d₆) δ (ppm): 1.94-2.01 (2H, m), 2.43 (2H, t, J=7.2 Hz),2.50 (6H, s), 4.33 (2H, t, J=7.2 Hz), 6.64 (1H, d, J=5.2 Hz), 7.04-7.46(4H, m), 7.61 (1H, s), 8.09-8.34 (2H, m), 8.74-8.78 (2H, m), 9.06 (1H,brs), 9.14 (1H, brs).

Example 50N-(4-(6-Cyano-7-(3-(diethylamino)propoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-(2,4-difluorophenyl)urea

The title compound (43 mg) was obtained from sodium6-cyano-4-(4-((2,4-difluoroanilino)carbonyl)amino-3-fluorophenoxy)-7-quinolinolate(95 mg), by the same procedure as in Example 7.

¹H-NMR (DMSO-d₆) δ (ppm): 0.97 (6H, t, J=7.8 Hz), 1.88-1.98 (2H, m),2.45-2.52 (4H, m), 2.61 (2H, t, J=7.8 Hz), 4.33 (2H, t, J=7.8 Hz), 6.63(1H, d, J=5.9 Hz), 7.03-7.45 (4H, m), 7.60 (1H, s), 8.09-8.17 (1H, m),8.28 (1H, t, J=11.5 Hz), 8.74-8.78 (2H, m), 9.03 (1H, brs), 9.11 (1H,brs).

Example 51N-(4-(6-Cyano-7-(4-(dimethylamino)butoxy)-4-quinolyl)oxyphenyl)-N′-(4-methoxyphenyl)urea

N-(4-(6-Cyano-7-(4-chlorobutoxy)-4-quinolyl)oxyphenyl)-N′-(4-methoxyphenyl)urea(120 mg) was dissolved in dimethylformamide (3 ml), and then a 50%dimethylamine solution (93 μl) was added and the mixture was heated andstirred at 70° C. for 5 hours. The reaction solution was poured intosaturated brine and extracted with ethyl acetate, and the organic layerwas dried over magnesium sulfate and concentrated. The residue waspassed through NH silica gel (Fuji Silysia Chemical) and eluted with asolvent (ethyl acetate), and then further eluted with another solvent(ethyl acetate:methanol=10:1) and concentrated. The obtained solid waspassed through Merck Silica Gel using tetrahydrofuran, and after elutingthe insoluble portion with tetrahydrofuran and ethyl acetate, it wasfurther eluted with solvents(tetrahydrofuran:methanol:triethylamine=10:1:1, ethylacetate:methanol:triethylamine=10:1:1) and concentrated to obtain 10 mgof the title compound as a solid.

¹H-NMR (DMSO-d₆) δ (ppm): 1.71-1.78 (2H, m), 1.82-1.91 (2H, m), 2.42(6H, s), 2.64-2.72 (2H, m), 3.72 (3H, s), 4.33 (2H, t, J=6.0 Hz), 6.54(1H, d, J=5.2 Hz), 6.88 (2H, d, J=8.8 Hz), 7.23 (2H, d, J=8.8 Hz), 7.37(2H, d, J=8.8 Hz), 7.60 (2H, d, J=8.8 Hz), 7.61 (1H, s), 8.64 (1H, brs),8.73 (1H, d, J=5.2 Hz), 8.78 (1H, s), 8.91 (1H, brs).

Example 52N-(4-(6-Cyano-7-(4-morpholinobutoxy)-4-quinolyl)oxyphenyl)-N′-4-methoxyphenyl)urea

The title compound (11 mg) was obtained fromN-(4-(6-cyano-7-(4-chlorobutoxy)-4-quinolyl)oxyphenyl)-N′-(4-methoxyphenyl)urea(110 mg), in the same manner as Example 51.

¹H-NMR (DMSO-d₆) δ (ppm): 1.65-1.77 (2H, m), 1.84-1.93 (2H, m),2.32-2.48 (6H, m), 3.51-3.66 (4H, m), 3.72 (3H, s), 4.33 (2H, t, J=6.0Hz), 6.53 (1H, d, J=4.8 Hz), 6.88 (2H, d, J=8.4 Hz), 7.24 (2H, d, J=8.4Hz), 7.37 (2H, d, J=8.4 Hz), 7.60 (2H, d, J=8.4 Hz), 7.61 (1H, s), 8.57(1H, brs), 8.73 (1H, d, J=4.8 Hz), 8.78 (1H, s), 8.82 (1H, brs).

Example 53N-(4-(6-Cyano-7-(3-(1-(4-ethyl)piperazino)propoxy)-4-quinolyl)oxyphenyl)-N′-(4-methoxyphenyl)urea

The title compound (16 mg) was obtained fromN-(4-(6-cyano-7-(3-chloropropoxy)-4-quinolyl)oxyphenyl)-N′-(4-methoxyphenyl)urea(150 mg), in the same manner as Example 51.

¹H-NMR (DMSO-d₆) δ (ppm): 0.98 (3H, t, J=7.2 Hz), 1.91-2.06 (2H, m),2.26-2.48 (12H, m), 3.72 (3H, s), 4.33 (2H, t, J=6.0 Hz), 6.53 (1H, d,J=5.2 Hz), 6.88 (2H, d, J=8.8 Hz), 7.23 (2H, d, J=8.8 Hz), 7.37 (2H, d,J=8.8 Hz), 7.59 (1H, s), 7.60 (2H, d, J=8.8 Hz), 8.58 (1H, brs), 8.73(1H, d, J=5.2 HZ), 8.76 (1H, s), 8.83 (1H, brs).

Example 54N-(4-(6-Cyano-7-(2-(4-morpholino)ethoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-(2,4-difluorophenyl)urea

The title compound (10 mg) was obtained from sodium6-cyano-4-(4-((2,4-difluoroanilino)carbonyl)amino-3-fluorophenoxy)-7-quinolinolate(200 mg), by the same procedure as in Example 7.

¹H-NMR (DMSO-d₆) δ (ppm): 2.56 (4H, t, J=4.4 Hz), 2.83 (2H, t, J=5.6Hz), 3.59 (4H, t, J=4.4 Hz), 4.43 (2H, t, J=5.6 Hz), 6.64 (1H, d, J=5.2Hz), 7.04-7.10 (1H, m), 7.14-7.19 (1H, m), 7.30-7.36 (1H, m), 7.42 (1H,dd, J=2.8 Hz, J=12 Hz), 7.66 (1H, s), 8.10-8.16 (1H, m), 8.28 (1H, t,J=9.2 HZ), 8.75 (1H, s), 8.76 (1H, d, J=5.2 Hz), 9.02-9.05 (1H, m),9.09-9.13 (1H, m).

Example 55N-(4-(6-Cyano-7-(3-cyanopropoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-(2,4-difluorophenyl)urea

The title compound (15 mg) was obtained from sodium6-cyano-4-(4-((2,4-difluoroanilino)carbonyl)amino-3-fluorophenoxy)-7-quinolinolate(300 mg), in the same manner as Example 7.

¹H-NMR (DMSO-d₆) δ (ppm): 2.14-2.21 (2H, m), 2.73 (2H, t, J=7.2 Hz),4.38 (2H, t, J=6.4 Hz), 6.65 (1H, d, J=5.2 Hz), 7.04-7.11 (1H, m),7.15-7.19 (1H, m), 7.31-7.37 (1H, m), 7.43 (1H, dd, J=2.8 Hz, J=11.6Hz), 7.67 (1H, s), 8.10-8.16 (1H, m), 8.29 (1H, t, J=9.2 HZ), 8.77 (1H,d, J=5.2 Hz), 8.79 (1H, s), 9.03-9.06 (1H, m), 9.11-9.14 (1H, m).

Example 56N-(4-6-Cyano-7-(2-(methylthio)ethoxy-4-quinolyl)oxy-2-fluorophenyl)-N′-(2,4-difluorophenyl)urea

The title compound (95 mg) was obtained from sodium6-cyano-4-(4-((2,4-difluoroanilino)carbonyl)amino-3-fluorophenoxy)-7-quinolinolate(130 mg), in the same manner as Example 7.

¹H-NMR (DMSO-d₆) δ (ppm): 2.25 (3H, s), 2.99 (2H, t, J=6.0 Hz), 4.49(2H, t, J=6.0 Hz), 6.64 (1H, d, J=5.2 Hz), 7.04-7.11 (1H, m), 7.15-7.19(1H, m), 7.30-7.37 (1H, m), 7.43 (1H, dd, J=2.4 Hz, J=11.6 Hz), 7.66(1H, s), 8.09-8.17 (1H, m), 8.29 (1H, t, J=9.2 Hz), 8.76 (1H, d, J=5.2Hz), 8.77 (1H, s), 9.01-9.05 (1H, m), 9.09-9.13 (1H, m).

Example 57N-(4-(6-Cyano-7-(2-(methylsulfonyl)ethoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-(2,4-difluorophenyl)urea

N-(4-(6-Cyano-7-(2-(methylthio)ethoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-(2,4-difluorophenyl)urea(84 mg) was dissolved in a methanol (1 ml) and methylene chloride (5 ml)mixed solvent, 2 equivalents of meta-perbenzoic acid was added whilestirring at 0° C., and the mixture was stirred for 30 minutes. Thereaction solution was poured into a saturated aqueous sodium bicarbonatesolution and extracted with ethyl acetate, and the organic layer wasdried over magnesium sulfate and then concentrated. The residue waspassed through NH silica gel (Fuji Silysia Chemical), eluted with asolvent (ethyl acetate:hexane=10:1) and concentrated to obtain 21 mg ofthe title compound.

¹H-NMR (DMSO-d₆) δ (ppm): 3.02 (3H, s), 3.79 (2H, t, J=4.8 Hz), 4.67(2H, t, J=4.8 Hz), 6.67 (1H, d, J=5.2 Hz), 7.04-7.10 (1H, m), 7.15-7.19(1H, m), 7.31-7.34 (1H, m), 7.43 (1H, dd, J=2.8 Hz, J=12 Hz), 7.73 (1H,s), 8.10-8.16 (1H, m), 8.28 (1H, t, J=9.2 HZ), 8.79 (1H, d, J=5.2 Hz),8.81 (1H, s), 9.02-9.05 (1H, m), 9.11-9.14 (1H, m).

Example 58N-(4-(6-Cyano-7-(2-(methylthio)ethoxy)-4-quinolyl)oxyphenyl)-N′-(4-fluorophenyl)urea

The title compound (112 mg) was obtained from sodium6-cyano-4-(4-((2,4-difluoroanilino)carbonyl)amino-3-fluorophenoxy)-7-quinolinolate(300 mg), in the same manner as Example 7.

¹H-NMR (DMSO-d₆) δ (ppm): 2.25 (3H, s), 2.99 (2H, t, J=6.0 Hz), 4.49(2H, t, J=6.0 Hz), 6.54 (1H, d, J=5.2 Hz), 7.13 (2H, t, J=8.8 Hz), 7.25(2H, d, J=8.8 Hz), 7.46-7.51 (2H, m), 7.61 (2H, d, J=8.8 Hz), 7.65 (1H,s), 8.74 (1H, d, J=5.2 Hz), 8.78 (1H, s), 8.82 (1H, brs), 8.91 (1H,brs).

Example 59N-(4-(6-Cyano-7-(2-(methylsulfonyl)ethoxy)-4-quinolyl)oxyphenyl)-N′-(4-fluorophenyl)urea

The title compound (11 mg) was obtained fromN-(4-(6-cyano-7-(2-(methylthio)ethoxy)-4-quinolyl)oxyphenyl)-N′-(4-fluorophenyl)urea(100 mg), in the same manner as Example 56.

¹H-NMR (DMSO-d₆) δ (ppm): 3.20 (3H, s), 3.79 (2H, t, J=5.6 Hz), 4.69(2H, t, J=5.6 Hz), 6.57 (1H, d, J=5.2 Hz), 7.13 (2H, t, J=8.8 Hz), 7.25(2H, d, J=8.8 Hz), 7.46-7.52 (2H, m), 7.62 (2H, d, J=8.8 Hz), 7.72 (1H,s), 8.76 (1H, d, J=5.2 Hz), 8.82 (1H, s), 8.90 (1H, brs), 8.99 (1H,brs).

Example 60N-(4-(6-Chloro-5,7-dimethoxy-4-quinolyl)oxy-2-fluorophenyl)-N′-(2,4-difluorophenyl)urea

The title compound (173 mg) was obtained from4-(4-amino-3-fluorophenoxy)-6-chloro-5,7-dimethoxyquinoline (235 mg) and2,4-difluorophenyl isocyanate, in the same manner as Example 10.

¹H-NMR (DMSO-d₆) δ (ppm): 3.93 (3H, s), 4.07 (3H, s), 6.67 (1H, d, J=5.2Hz), 6.91-6.96 (1H, m), 7.00 (1H, s), 7.03-7.09 (1H, m), 7.20 (1H, dd,J=2.8 Hz, J=8.0 Hz), 7.30-7.37 (1H, m), 8.08-8.20 (2H, m), 8.69 (1H, d,J=5.2 Hz), 9.01 (1H, brd, J=2.0 Hz), 9.04 (1H, brd, J=2.0 Hz).

Example 61N-(4-(6-Cyano-7-methoxy-4-quinolyl)oxy-2-fluorophenyl)-N′-(2,4-difluorophenyl)urea

The title compound (130 mg) was obtained from4-(4-amino-3-fluorophenoxy)-6-cyano-7-methoxyquinoline (238 mg) and2,4-difluorophenyl isocyanate, in the same manner as Example 10.

¹H-NMR (DMSO-d₆) δ (ppm): 4.08 (3H, s), 6.64 (1H, d, J=5.2 Hz),7.04-7.10 (1H, m), 7.15-7.19 (1H, m), 7.31-7.37 (1H, m), 7.43 (1H, dd,J=2.8 Hz, J=12 Hz), 7.63 (1H, s), 8.13 (1H, dt, J=6.4 Hz, J=9.2 Hz),8.29 (1H, t, J=9.2 Hz), 8.77 (1H, d, J=5.2 Hz), 8.78 (1H, s), 9.05 (1H,brs), 9.13 (1H, brs).

Example 62N-(4-(6-Cyano-7-methoxy-4-quinolyl)oxyphenyl)-N′-(4-methoxyphenyl)urea

The title compound (55 mg) was obtained from4-amino(4-aminophenoxy)-6-cyano-7-methoxyquinoline (170 mg) and4-methoxyphenyl isocyanate, in the same manner as Example 10.

¹H-NMR (DMSO-d₆) δ (ppm): 3.72 (3H, s), 4.07 (3H, s), 6.54 (1H, d, J=5.2Hz), 6.88 (2H, d, J=8.8 Hz), 7.24 (2H, d, J=8.8 Hz), 7.37 (2H, d, J=8.8Hz), 7.60 (2H, d, J=8.8 Hz), 7.61 (1H, s), 8.62 (1H, brs), 8.74 (1H, d,J=5.2 Hz), 8.78 (1H, s), 8.87 (1H, brs).

Example 63N-(4-(6-Cyano-7-(2-(4-morpholino)ethoxy)-4-quinolyl)oxyphenyl)-N′-(4-methoxyphenyl)urea

The title compound was obtained from sodium6-cyano-4-(4-((4-methoxyanilino)carbonyl)aminophenoxy)-7-quinolinolate,in the same manner as Example 7.

¹H-NMR (DMSO-d₆) δ (ppm): 2.50-2.55 (4H, m), 2.87 (2H, t, J=5.6 Hz),3.57 (4H, t, J=4.4 Hz), 3.60 (3H, s), 4.38 (2H, t, J=5.6 Hz), 6.85 (2H,d, J=8.8 Hz), 7.02 (1H, s), 7.06 (1H, d, J=5.2 Hz), 7.21 (2H, d, J=8.8Hz), 7.36 (2H, d, J=8.8 Hz), 7.58 (2H, d, J=8.8 Hz), 8.65 (1H, s), 8.68(1H, brs), 8.73 (1H, d, J=5.2 Hz), 8.92 (1H, brs)

Example 64N-(4-(6-Cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)-N′-cyclohexylurea

The title compound (25 mg) was obtained from4-(4-aminophenoxy)-6-cyano-7-(2-methoxyethoxy)quinoline (60 mg) andcyclohexyl isocyanate, in the same manner as Example 10.

¹H-NMR (DMSO-d₆) δ (ppm): 1.12-1.24 (3H, m), 1.26-1.38 (2H, m),1.51-1.59 (1H, m), 1.63-1.72 (2H, m), 1.78-1.86 (2H, m), 3.38 (3H, s),3.42-3.52 (1H, m), 3.78-3.80 (2H, m), 4.42-4.44 (2H, m), 6.18 (1H, brd,J=8.0 Hz), 6.50 (1H, d, J=5.2 Hz), 7.18 (2H, d, J=9.2 Hz), 7.53 (2H, d,J=9.2 Hz), 7.63 (1H, s), 8.55 (1H, brs), 8.72 (1H, d, J=5.2 Hz), 8.77(1H, s).

Example 65N-(4-(6-Cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)-N′-phenylurea

4-(4-Aminophenoxy)-6-cyano-7-(2-methoxyethoxy)quinoline (600 mg) wassuspended in toluene (15 ml), and the suspension was heated to refluxfor dissolution, after which phenyl isocyanate (292 μl) was addeddropwise and the mixture was heated to reflux for 30 minutes. Aftercooling, the precipitated solid was filtered out, washed with ether andethyl acetate and dried to obtain 760 mg of the title compound.

¹H-NMR (DMSO-d₆) δ (ppm): 3.38 (3H, s), 3.78-3.81 (2H, m), 4.42-4.45(2H, m), 6.54 (1H, d, J=5.2 Hz), 6.98 (1H, t, J=7.2 Hz), 7.24-7.31 (4H,m), 7.47 (2H, d, J=7.2 Hz), 7.62 (2H, d, J=8.8 Hz), 7.64 (1H, s), 8.74(1H, d, J=5.2 Hz), 8.79 (1H, s), 8.85 (1H, brs), 8.99 (1H, brs).

Example 66N-(4-(6-Cyano-7-(2-methoxyethoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-(2,4-difluorophenyl)urea

4-(4-Amino-3-fluorophenoxy)-6-cyano-7-(2-methoxyethoxy)quinoline (352mg) was suspended in toluene (20 ml) and the suspension was heated toreflux for dissolution, after which 2,4-difluorophenyl isocyanate (236μl) was added dropwise and the mixture was heated to reflux for 30minutes. After cooling, the precipitated solid was filtered out, washedwith ether and ethyl acetate and dried to obtain 380 mg of the titlecompound.

¹H-NMR (DMSO-d₆) δ (ppm): 3.38 (3H, s), 3.78-3.81 (2H, m), 4.42-4.46(2H, m), 6.64 (1H, d, J=5.2 Hz), 7.04-7.11 (1H, m), 7.15-7.19 (1H, m),7.31-7.37 (1H, m), 7.43 (1H, dd, J=2.8 Hz, J=8.0 Hz), 7.66 (1H, s), 8.13(1H, dt, J=6 Hz, J=9.2 Hz), 8.28 (1H, t, J=9.2 Hz), 8.76 (1H, d, J=5.2Hz), 8.77 (1H, s), 9.05 (1H, brs), 9.13 (1H, brs).

Example 67N-(4-(6-Cyano-7-(2-methoxyethoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-(methoxyphenyl)urea

The title compound (570 mg) was obtained from4-(4-amino-3-fluorophenoxy)-6-cyano-7-(2-methoxyethoxy)quinoline (620mg) and 4-methoxyphenyl isocyanate, in the same manner as Example 10.

¹H-NMR (DMSO-d₆) δ (ppm): 3.38 (3H, s), 3.73 (3H, s), 3.78-3.81 (2H, m),4.43-4.45 (2H, m), 6.63 (1H, d, J=5.2 Hz), 6.89 (2H, d, J=8.8 Hz),7.13-7.17 (1H, m), 7.37 (2H, d, J=8.8 Hz), 7.41 (1H, dd, J=2.8 Hz,J=11.6 Hz), 7.65 (1H, s), 8.28 (1H, t, J=8.8 Hz), 8.60 (1H, brs), 8.76(1H, d, J=5.2 Hz), 8.77 (1H, s), 8.94 (1H, brs).

Example 68N-(4-(6-Cyano-7-(methoxyethoxy)-4-quinolyl)oxyphenyl)-N′-(4-methoxyphenyl)urea

The title compound (450 mg) was obtained from4-(4-aminophenoxy)-6-cyano-7-(2-methoxyethoxy)quinoline (890 mg) and4-methoxyphenyl isocyanate, in the same manner as Example 10.

¹H-NMR (DMSO-d₆) δ (ppm): 3.36 (3H, s), 3.70 (3H, s), 3.76-3.79 (2H, m),4.40-4.42 (2H, m), 6.51 (1H, d, J=5.6 Hz), 6.86 (2H, d, J=8.8 Hz), 7.22(2H, d, J=8.8 Hz), 7.35 (2H, d, J=8.8 Hz), 7.58 (2H, d, J=8.8 Hz), 7.62(1H, s), 8.53 (1H, brs), 8.71 (1H, d, J=5.6 Hz), 8.76 (1H, s), 8.80 (1H,brs).

Example 69 N-((4-Pyrimidyl)oxyphenyl)-N′-(4-methoxyphenyl)urea

Palladium hydroxide (20 mg) was added to solution of6-chloro-4-(4-nitrophenoxy)pyrimidine (300 mg) in an ethyl acetate (10ml)-methanol (10 ml) mixed solvent, and the mixture was stirred for 13hours at room temperature under a hydrogen atmosphere at normalpressure. The reaction solution was filtered, the filtrate wasconcentrated, and the residue was passed through NH silica gel (FujiSilysia Chemical). Elution was performed with a solvent (ethylacetate:hexane=1:2) to obtain 70 mg of 4-(4-aminophenoxy)pyrimidine. Thetitle compound (107 mg) was obtained from the obtained4-(4-aminophenoxy)pyrimidine (70 mg) and 4-methoxyphenyl isocyanate, inthe same manner as Example 10.

¹H-NMR (DMSO-d₆) δ (ppm): 3.72 (3H, s), 6.87 (2H, d, J=8.8 Hz), 7.09(1H, dd, J=1.6 Hz, J=5.6 Hz), 7.12 (2H, d, J=8.8 Hz), 7.36 (2H, d, J=8.8Hz), 7.51 (2H, d, J=8.8 Hz), 8.56 (1H, s), 8.66 (1H, d, J=5.6 HZ),8.74-8.76 (2H, m).

Example 70N-(4-(6-Cyano-7-(3-methoxycarbonylpropoxy)-4-quinolyl)oxyphenyl)-N′-(4-methoxyphenyl)urea

The title compound was obtained from sodium6-cyano-4-(4-((4-methoxyanilino)carbonyl)aminophenoxy)-7-quinolinolate,in the same manner as Example 7.

¹H-NMR (DMSO-d₆) δ (ppm): 2.09 (2H, tt, J=6.4 Hz, J=6.4 Hz), 2.56 (2H,t, J=6.4 Hz), 3.62 (3H, s), 3.71 (3H, s), 4.31 (2H, t, J=6.4 Hz), 6.52(1H, d, J=5.2 Hz), 6.86 (2H, d, J=8.8 Hz), 7.22 (2H, d, J=8.8 Hz), 7.35(2H, d, J=8.8 Hz), 7.57 (2H, d, J=8.8 Hz), 7.59 (1H, s), 8.50 (1H, s),8.72 (1H, d, J=5.2 Hz) 8.74 (1H, s), 8.75 (1H, s).

Example 71N-(4-(6-Cyano-7-(3-carboxypropoxy)-4-quinolyl)oxyphenyl)-N′-(4-methoxyphenyl)urea

N-(4-(6-Cyano-7-(3-methoxycarbonylpropoxy)-4-quinolyl)oxyphenyl)-N′-(4-methoxyphenyl)urea(100 mg) was added to a methanol (16 ml) and 2N aqueous sodium hydroxide(3 ml) mixed solvent, and the mixture was heated and stirred at 80° C.for 35 minutes. The reaction solution was filtered, and then 1.2 ml ofaqueous 5N hydrochloric acid was added. The precipitated solid wasfiltered out and washed with methanol and then ether to obtain 50 mg ofthe target substance as a light yellow solid.

¹H-NMR (DMSO-d₆) δ (ppm): 2.05 (2H, tt, J=6.4 Hz, J=6.4 Hz), 2.47 (2H,t, J=6.4 Hz), 3.70 (3H, s), 4.31 (2H, t, J=6.4 Hz), 6.52 (1H, d, J=5.2Hz), 6.86 (2H, d, J=8.8 Hz), 7.22 (2H, d, J=8.8 Hz), 7.35 (2H, d, J=8.8Hz), 7.57 (2H, d, J=8.8 Hz), 7.59 (1H, s), 8.50 (1H, s), 8.71 (1H, d,J=5.2 Hz) 8.75 (1H, s), 8.76 (1H, s).

Example 72N-(4-(6-Cyano-7-(2-(2-hydroxyethoxy)ethoxy)-4-quinolyl)oxyphenyl)-N′-(4-methoxyphenyl)urea

The title compound was obtained from sodium6-cyano-4-(4-((4-methoxyanilino)carbonyl)aminophenoxy)-7-quinolinolate,in the same manner as Example 7.

¹H-NMR (DMSO-d₆) δ (ppm): 3.54-3.57 (4H, m), 3.72 (3H, s), 3.87-3.90(2H, m), 4.41-4.45 (2H, m), 4.62-4.65 (1H, m), 6.54 (1H, d, J=5.2 Hz),6.87 (2H, d, J=8.8 Hz), 7.24 (2H, d, J=8.8 Hz), 7.38 (2H, d, J=8.8 Hz),7.60 (2H, d, J=8.8 Hz), 7.64 (1H, s), 8.62 (1H, brs), 8.74 (1H, d, J=5.2Hz), 8.78 (1H, s), 8.87 (1H, brs).

Example 73N-(4-(6-Cyano-7-(3-(diethylamino)propoxy)-4-quinolyloxy)phenyl)-N′-(3-(methylsulfonyl)phenyl)urea

The title compound (8.8 mg, 0.015 mmol, 6.0%) was obtained as lightbrown crystals fromN-4-((6-cyano-7-hydroxy-4-quinolyl)oxy)phenyl-N′-(3-(methylsulfonyl)phenyl)urea(119 mg, 0.25 mmol), by the same procedure as in Example 7.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.95 (6H, t, J=7.2 Hz), 1.87-1.95(2H, m), 2.40-2.70 (6H, m), 3.18 (3H, s), 4.29-4.33 (2H, m), 6.51 (1H,d, J=5.2 Hz), 7.25 (2H, d, J=8.8 Hz), 7.49-7.68 (6H, m), 8.16 (1H, brs),8.71 (1H, d, J=5.2 Hz), 8.75 (1H, s), 9.02 (1H, brs), 9.21 (1H, brs).

Example 74N-(4-(6-Cyano-7-(3-(4-morpholino)propoxy)-4-quinolyl)oxyphenyl)-N′-(3-(methylsulfonyl)phenyl)urea

The title compound (81 mg, 0.135 mmol, 53.7%) was obtained as lightyellow crystals fromN-4-((6-cyano-7-hydroxy-4-quinolyl)oxy)phenyl-N′-(3-(methylsulfonyl)phenyl)urea(119 mg, 0.25 mmol), by the same procedure as in Example 7.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.95-2.04 (2H, m), 2.34-2.60 (6H, m),3.18 (3H, s), 3.54-3.60 (4H, m), 4.30-4.36 (2H, m), 6.52 (1H, d, J=5.2Hz), 7.25 (2H, d, J=8.8 Hz), 7.50-7.68 (6H, m), 8.16 (1H, s), 8.72 (1H,d, J=5.2 Hz), 8.75 (1H, s), 8.95 (1H, s), 9.15 (1H, s).

Example 75N-(4-(6-Cyano-7-(3-(diethylamino)propoxy)-4-quinolyloxy)phenyl)-N′-phenylurea

The title compound (70 mg, 0.137 mmol, 27.5%) was obtained as lightbrown crystals from sodium4-(4-((anilinocarbonyl)amino)phenoxy)-6-cyano-7-quinolinolate (210 mg,0.50 mmol), by the same procedure as in Example 7.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.95 (6H, t, J=7.2 Hz), 1.85-1.95(2H, m), 2.40-2.55 (4H, m), 2.60 (2H, t, J=6.8 Hz), 4.31 (2H, t, J=6.0Hz), 6.51 (1H, d, J=5.2 Hz), 6.96 (1H, m), 7.22-7.30 (4H, m), 7.45 (2H,d, J=8.0 Hz), 7.56-7.61 (3H, m), 8.70-8.72 (2H, m), 8.75 (1H, s), 8.84(1H, s).

Example 76N-(4-(6-Cyano-7-(3-(4-morpholino)propoxy)-4-quinolyl)oxyphenyl)-N′-phenylurea

The title compound (67 mg, 0.128 mmol, 51.0%) was obtained as lightyellow crystals from sodium4-(4-((anilinocarbonyl)amino)phenoxy)-6-cyano-7-quinolinolate (105 mg,0.25 mmol), by the same procedure as in Example 7.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.92-2.02 (2H, m), 2.35-2.57 (6H, m),3.55-3.57 (4H, m), 4.30-4.34 (2H, m), 6.51 (1H, d, J=5.6 Hz), 6.96 (1H,t, J=7.2 Hz), 7.22-7.30 (4H, m), 7.45 (2H, d, J=7.6 Hz), 7.58-7.61 (3H,m), 8.69-8.72 (2H, m), 8.75 (1H, s), 8.83 (1H, s).

Example 77N-(4-(6-Cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)-N′-(1H-[d]imidazol-2-yl)urea

The title compound (71 mg, 0.14 mmol, 64.7%) was obtained as whitecrystals from phenylN-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)carbamate (101mg, 0.222 mmol), by the same procedure as in Example 11.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.36 (3H, s), 3.75-3.79 (2H, m),4.40-4.43 (2H, m), 6.54 (1H, d, J=5.2 Hz), 7.04-7.07 (2H, m), 7.26 (2H,d, J=8.8 Hz), 7.34-7.37 (2H, m), 7.62 (1H, s), 7.73 (2H, d, J=8.8 Hz),8.72 (1H, d, J=5.2 Hz), 8.77 (1H, s).

Example 78N-(4-(6-Cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)-N′-(2-oxo-1,2,3,4-tetrahydro-6-quinolinyl)urea

The title compound (70 mg, 0.134 mmol, 60.9%) was obtained as whitecrystals from phenylN-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)carbamate (100mg, 0.220 mmol), by the same procedure as in Example 11.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.38-2.43 (2H, m), 2.81-2.85 (2H, m),3.36 (3H, s), 3.75-3.79 (2H, m), 4.40-4.43 (2H, m), 6.51 (1H, d, J=5.2Hz), 6.76 (1H, d, J=8.4 Hz), 7.16 (1H, dd, J=2.0, 8.4 Hz), 7.22 (2H, dd,J=8.8 Hz), 7.30 (1H, s), 7.58 (2H, d, J=8.8 Hz), 7.62 (1H, s), 8.52 (1H,s), 8.71 (1H, d, J=5.2 Hz), 8.75 (2H, s), 9.95 (1H, s).

Example 79N-(4-(6-Cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)-N′-(4-acetamidephenyl)urea

The title compound (100 mg, 0.197 mmol, 89.6%) was obtained as whitecrystals from phenylN-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)carbamate (100mg, 0.220 mmol), by the same procedure as in Example 11.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.00 (3H, s), 3.36 (3H, s), 3.76-3.79(2H, m), 4.40-4.43 (2H, m), 6.52 (1H, d, J=5.2 Hz), 7.23 (2H, d, J=8.8Hz), 7.35 (2H, d, J=8.8 Hz), 7.46 (2H, d, J=8.8 Hz), 7.58 (2H, d, J=8.8Hz), 7.62 (1H, s), 8.59 (1H, s), 8.72 (1H, d, J=5.2 Hz), 8.76 (1H, s),8.77 (1H, s), 9.80 (1H, s).

Example 80N-(4-(6-Cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)-N′-(3-acetamidephenyl)urea

The title compound (95 mg, 0.186 mmol, 84.9%) was obtained as whitecrystals from phenylN-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)carbamate (100mg, 0.220 mmol), by the same procedure as in Example 11.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.02 (3H, s), 3.36 (3H, s), 3.76-3.79(2H, m), 4.40-4.43 (2H, m), 6.52 (1H, d, J=5.6 Hz), 7.15-7.20 (3H, m),7.23 (2H, d, J=8.8 Hz), 7.59 (2H, d, J=8.8 Hz), 7.62 (1H, s), 7.76 (1H,s), 8.71-8.76 (4H, m), 9.90 (1H, s).

Example 81N-(4-(6-Cyano-7-benzyloxy-4-quinolyl)oxy-2-fluorophenyl)-N′-(2,4-difluorophenyl)urea

N-(2,4-Difluorophenyl)-N′-(2-fluoro-4-hydroxyphenyl)urea (227 mg, 0.8058mmol) and 4-chloro-6-cyano-7-benzyloxyquinoline (250 mmol, 0.8482 mmol)were used for reaction in the same manner as the second method inExample 86, and after cooling, extraction and washing with water, thesolvent was distilled off under reduced pressure and the obtainedcrystals were suspended in diethyl ether, washed and filtered. They werethen dissolved in tetrahydrofuran and filtered with silica gel, and thesolvent was distilled off under reduced pressure. These crystals werethen suspended in diethyl ether, washed with water and filtered, andthen washed with diethyl ether and dried by aspiration to obtain thetitle compound (70 mg, 0.1295 mmol, 16.07%) as light brown crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 5.45 (2H, s), 6.63 (1H, d, J=5.4 Hz),7.05 (1H, m), 7.15 (1H, m), 7.29-7.46 (5H, m), 7.54 (2H, d, J=7.6 Hz),7.71 (1H, s), 8.11 (1H, dt, J=6.0 Hz, 9.2 Hz), 8.27 (1H, d, J=9.2 Hz),8.74 (1H, d, J=5.4 Hz), 8.77 (1H, s), 8.99 (1H, s), 9.07 (1H, s).

Example 82N-(4-(7-(Benzyloxy)-6-cyano-4-quinolyl)oxyphenyl-N′-(2-thiazolyl)urea

The title compound (3.19 g, 6.46 mmol, 91%) was obtained as light browncrystals from 4-(4-aminophenoxy)-7-(benzyloxy)-6-cyanoquinoline (2.61 g,7.10 mmol) and phenyl N-(2-thiazolyl)carbamate (1.88 g, 8.54 mmol), bythe same procedure as in Example 34.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 5.47 (2H, s), 6.55 (1H, d, J=5.3 Hz),7.12 (1H, d, J=3.5 Hz), 7.29 (2H, d, J=8.7 Hz), 7.36-7.58 (6H, m), 7.65(2H, d, J=8.7 Hz), 7.72 (1H, s), 8.74 (1H, d, J=5.3 Hz), 8.80 (1H, s),9.18 (1H, s).

Example 83N-(4-(6-Cyano-7-hydroxy-4-quinolyl)oxyphenyl)-N′-(2-thiazolyl)urea

The N-(4-(7-(benzyloxy)-6-cyano-4-quinolyl)oxyphenyl-N′-(2-thiazole)urea(3.09 g, 7.66 mmol) obtained in Example 82 was dissolved intrifluoroacetic acid (25 ml) and thioanisole (4.50 ml, 38.3 mmol), andthe mixture was stirred at 65° C. for 15 hours. The reaction solutionwas concentrated under reduced pressure, and then a 5% aqueous sodiumbicarbonate solution and diethyl ether were added to the resultingresidue, the mixture was stirred, and the crystals were filtered out andwashed with water and diethyl ether and then dried under reducedpressure. The crude product was suspended in a hexane-ethyl acetatemixed solvent and subjected to sonication, after which the crystals werefiltered, washed with diethyl ether and blow-dried at room temperatureto obtain the title compound (1.94 g, 4.80 mmol, 63%) as yellowcrystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 6.44 (1H, d, J=5.2 Hz), 7.12 (1H, d,J=3.7 Hz), 7.28 (2H, d, J=7.8 Hz), 7.39 (1H, d, J=3.7 Hz), 7.42 (1H, s),7.64 (2H, d, J=7.8 Hz), 8.65 (1H, d, J=5.2 Hz), 8.68 (1H, s), 9.14 (1H,s).

Example 84N-(4-(6-Cyano-7-(3-(diethylamino)propoxy)-4-quinolyloxy)phenyl-N′-(2-thiazolyl)urea

The title compound (26 mg, 0.0503 mmol, 20%) was obtained as colorlesscrystals from theN-(4-(6-cyano-7-hydroxy-4-quinolyl)oxyphenyl)-N′-(2-thiazolyl)urea (101mg, 0.250 mmol) obtained in Example 83, by the same procedure as inExample 7.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.05 (6H, t, J=7.2 Hz), 2.03-2.12 (2H,m), 2.58 (4H, q, J=7.2 Hz), 2.71 (2H, t, J=7.0 Hz), 4.28 (2H, t, J=6.2Hz), 6.47 (1H, d, J=5.3 Hz), 6.92 (1H, d, J=3.7 Hz), 7.17 (2H, d, J=8.8Hz), 7.43 (1H, d, J=3.7 Hz), 7.47 (1H, s), 7.67 (2H, d, J=8.8 Hz), 8.65(1H, d, J=5.3 Hz), 8.67 (1H, s).

Example 85N-(4-(6-Cyano-7-(3-(4-morpholino)propoxy)-4-quinolyl)oxyphenyl)-N′-(2-thiazolyl)urea

The title compound (19 mg, 0.0358 mmol, 14%) was obtained as colorlesscrystals from theN-(4-(6-cyano-7-hydroxy-4-quinolyl)oxyphenyl)-N′-(2-thiazolyl)urea (101mg, 0.250 mmol) obtained in Example 83, by the same procedure as inExample 7.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 2.08-2.16 (2H, m), 2.46-2.52 (4H, m),2.62 (2H, t, J=7.0 Hz), 3.70-3.76 (4H, m), 4.30 (2H, t, J=6.2 Hz), 6.47(1H, d, J=5.3 Hz), 6.92 (1H, d, J=3.7 Hz), 7.17 (2H, d, J=8.8 Hz), 7.42(1H, d, J=3.7 Hz), 7.48 (1H, s), 7.67 (2H, d, J=8.8 Hz), 8.66 (1H, d,J=5.3 Hz), 8.69 (1H, s).

Example 86N-(4-(6-Cyano-7-benzyloxy-4-quinolyl)oxyphenyl)-N′-(4-methoxyphenyl)urea

After adding toluene (60 ml) and acetonitrile (30 ml) to4-amino(4-aminophenoxy)-7-(benzyloxy)-6-cyanoquinoline (1.0 g) andrefluxing the mixture to dissolution, 4-methoxyphenyl isocyanate (0.53ml) was added while continuing reflux. After stirring for 1 hour withreflux, additional 4-methoxyphenyl isocyanate (0.30 ml) was added. Thiswas further stirred for 40 minutes with reflux and returned to roomtemperature. The precipitated crystals were filtered out and washed witha mixed solvent of toluene:acetonitrile=1:1 to obtain the title compound(0.60 g) as light brown crystals. The crystals which precipitated fromthe washing solution were filtered out to obtain more of the titlecompound (0.20 g) as light brown crystals.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 3.73 (3H, s), 5.98 (2H, s), 6.56 (1H,d, J=5.2 Hz), 6.89 (2H, d, J=9.3 Hz), 7.24 (2H, d, J=9.3 Hz), 7.33-7.65(9H, m), 7.72 (1H, s), 8.74 (1H, d, J=5.2 Hz), 8.82 (1H, s), 8.89 (1H,brs), 9.19 (1H, brs).

Example 86-2N-(4-(6-Cyano-7-benzyloxy-4-quinolyl)oxyphenyl)-N′-(4-methoxyphenyl)urea

After adding 1-methylpyrrolidone (3.4 ml) and diisopropylethylamine (3.6ml, 20.78 mmol) to N-(4-hydroxyphenyl)-N′-(4-methoxyphenyl)urea (4.25 g,16.46 mmol), the mixture was heated and stirred at 130° C. to completedissolution, and then 4-chloro-6-cyano-7-benzyloxyquinoline (5.10 g,17.32 mmol) was added and the mixture was stirred at 130° C. for 1.5hours and at 150° C. for 1 hour. Upon addition of diisopropylethylamine(1.2 ml, 6.93 mmol), the mixture was further stirred for 1 hour. Aftercooling and adding tetrahydrofuran and ethyl acetate, the mixture waswashed with saturated sodium bicarnobate water and saturated brine anddried over magnesium sulfate, and the solvent was distilled off underreduced pressure. The obtain crystals were washed with diethylether/hexane, acetonitrile/diethyl ether/hexane, methanol anddimethylsulfoxide/water, in that order. The obtained crystals weredissolved in tetrahydrofuran, filtered with silica gel (200 cc silicagel) and flushed with 3000 ml of tetrahydrofuran, and the solvent wasdistilled off under reduced pressure. The crystals were then washed withdiethyl ether, acetonitrile and diethyl ether:ethanol=5:1 and dried byaspiration to obtain the title compound (3.70 g, 7.1627 mmol, 43.52%) asbrown crystals.

Example 87 Sodium6-cyano-4-(4-((4-methoxyanilino)carbonyl)aminophenoxy)-7-quinolinolate

Trifluoroacetic acid (122 ml) and thioanisole (11.7 ml) were added toN-(4-(6-cyano-7-benzyloxy-4-quinolyl)oxyphenyl)-N′-(4-methoxyphenyl)urea(12.2 g), and the mixture was stirred at 50° C. overnight and at 40° C.for 24 hours. Upon confirming disappearance of the starting materials,the reaction system was concentrated under reduced pressure,tetrahydrofuran and saturated sodium bicarnobate water were added, andthe precipitated yellow crystals were filtered and dried under reducedpressure to obtain the title compound (6.8 g). Ether was further addedto the filtrate and the precipitated yellow crystals were filtered outand dried under reduced pressure to obtain more of the title compound(2.0 g).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 3.72 (3H, s), 6.56 (1H, d, J=6.1 Hz),6.88 (2H, d, J=8.7 Hz), 7.23 (2H, d, J=8.7 Hz), 7.37 (2H, d, J=8.7 Hz),7.44 (1H, s), 7.60 (2H, d, J=8.7 Hz), 8.57 (1H, s), 8.67 (1H, d, J=6.1Hz), 8.70 (1H, s), 8.82 (1H, s).

Example 88 Sodium6-cyano-4-(4-((4-fluoroanilino)carbonyl)aminophenoxy)-7-quinolinolate

4-(4-Aminophenoxy)-7-(benzyloxy)-6-cyanoquinoline (7.776 g, 21.2 mmol)was dissolved in a toluene (400 ml) and acetonitrile (200 ml) mixedsolvent, and then 4-fluorophenyl isocyanate (3.68 ml, 31.7 mmol) wasadded and the mixture was heated to reflux at 120° C. for 1 hour. Thereaction solution was concentrated under reduced pressure, the residuewas suspended in tetrahydrofuran (150 ml), and then hexane (150 ml) wasadded, sonication was performed, and the precipitated crystals werefiltered out and dried under reduced pressure to obtainN-(4-(7-(benzyloxy)-6-cyano-4-quinolyl)oxyphenyl)-N′-(4-fluorophenyl)urea(9.81 g, 19.4 mmol, 91.9%) as light brown crystals. These were dissolvedin trifluoroacetic acid (100 ml) and thioanisole (9.13 ml, 77.7 mmol)under a nitrogen atmosphere, and the solution was stirred at 60° C. for12 hours. The reaction solution was concentrated under reduced pressure,and after adding tetrahydrofuran (50 ml) and then 1N aqueous sodiumhydroxide (150 ml) and water (150 ml) to the residue, the mixture wasstirred and the precipitated crystals were filtered out and washed withwater, diethyl ether and ethyl acetate and dried at 70° C. to obtain thetitle compound (3.646 g, 8.36 mmol, 43.0%) as yellow crystals. negativeESI-MS 413 (M−Na)⁻

Example 89 Sodium6-cyano-4-(4-(2,4-difluoroanilino)carbonyl)amino-3-fluorophenoxy)-7-quinolinolate

A mixture of the 7-benzyloxy compound (1.1 g) obtained in Example 81,trifluoroacetic acid (10 ml) and thioanisole (1 ml) was heated andstirred in an oil bath at 63-67° C. for 16 hours. After completion ofthe reaction, the reaction solution was concentrated, a saturatedaqueous sodium bicarbonate solution was added, and the precipitatedsolid was filtered out. The obtained solid was washed with water, etherand ethyl acetate and dried to obtain the title compound in aquantitative amount.

¹H-NMR (DMSO-d₆) δ (ppm): 6.54 (1H, d, J=5.6 Hz), 7.04-7.10 (1H, m),7.14-7.17 (1H, m), 7.31-7.36 (1H, m), 7.40 (1H, dd, J=2.8 Hz, J=12 Hz),7.44 (1H, s), 8.10-8.16 (1H, m), 8.27 (1H, t, J=8.8 HZ), 8.67 (1H, s),8.68 (1H, d, J=5.2 Hz), 8.99-9.03 (1H, m), 9.07-9.11 (1H, m).

Example 90N-(4-(6-Cyano-7-(2-chloroethoxy)-4-quinolyl)oxyphenyl)-N′-(4-fluorophenyl)urea

N-(4-(6-Cyano-7-hydroxy-4-quinolyl)oxyphenyl)-N′-(4-fluorophenyl)urea(400 mg, 0.9166 mmol) was dissolved in dimethylformamide (5.0 ml), andthen 1-bromo-2-chloroethane (0.12 ml, 1.4479 mmol) and potassiumcarbonate (200 mg, 1.4479 mmol) were added and the mixture was heatedand stirred at 55° C. for 4 hours. After cooling, tetrahydrofuran andethyl acetate were added, the mixture was washed with saturated brineand dried over anhydrous magnesium sulfate, the solvent was distilledoff under reduced pressure, and the residue was subjected to NH silicagel column chromatography (ethyl acetate-methanol system). The obtainedcrystals were suspended in diethyl ether, the suspension was dilutedwith hexane, and the crystals were filtered out, washed with hexane anddried by aspiration to obtain the title compound (331 mg, 0.6941 mmol,75.72%) as light yellow crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 4.07 (2H, t, J=5.2 Hz), 4.59 (2H, t,J=5.2 Hz), 6.54 (1H, d, J=5.6 Hz), 7.12 (2H, t, J=9.0 Hz), 7.24 (2H, d,J=9.0 Hz), 7.44-7.48 (2H, m), 7.59 (2H, d, J=9.0 Hz), 7.65 (1H, s), 8.72(1H, s), 8.73 (1H, d, J=5.6 Hz), 8.78 (1H, s), 8.82 (1H, s).

Example 91N-(4-(6-Cyano-7-(2-chloroethoxy)-4-quinolyl)oxyphenyl)-N′-(4-methoxyphenyl)urea

The title compound (501 mg, 1.0247 mmol, 87.39%) was obtained as yellowcrystals fromN-(4-(6-cyano-7-hydroxy-4-quinolyl)oxyphenyl)-N′-(4-methoxyphenyl)urea(500 mg, 1.1725 mmol), in the same manner as Example 90.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.70 (3H, s), 4.06 (2H, t, J=5.0 Hz),4.59 (2H, t, J=5.0 Hz), 6.53 (1H, d, J=5.6 Hz), 6.86 (2H, d, J=9.2 Hz),7.22 (2H, d, J=9.2 Hz), 7.35 (2H, d, J=9.2 Hz), 7.58 (2H, d, J=9.2 Hz),7.65 (1H, s), 8.55 (1H, m), 8.73 (1H, d, J=5.6 Hz), 8.78 (1H, m), 8.88(1H, s).

Example 92N-(4-(6-Cyano-7-(2-chloroethoxy)-4-quinolyl)oxyphenyl)-N′-(2,4-difluorophenyl)urea

The title compound (227 mg, 0.4426 mmol, 66.45%) was obtained as lightyellow crystals fromN-(4-(6-cyano-7-hydroxy-4-quinolyl)oxyphenyl)-N′-(2,4-difluorophenyl)urea(300 mg, 0.6661 mmol), in the same manner as Example 90.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 4.07 (2H, t, J=5.0 Hz), 4.59 (2H, t,J=5.0 Hz), 6.64 (1H, d, J=5.4 Hz), 7.06 (1H, m), 7.16 (1H, m), 7.32 (1H,ddd, J=2.8 Hz, 8.8 Hz, 11.6 Hz), 7.41 (1H, dd, J=2.8 Hz, 11.6 Hz), 7.67(1H, s), 7.93 (1H, s), 8.12 (1H, m), 8.27 (1H, dt, J=4.0 Hz, 9.2 Hz),8.76 (1H, d, J=5.4 Hz), 8.77 (1H, s), 8.97-9.09 (1H, m).

Example 93N-(4-(6-Cyano-7-(4-chlorobutoxy)-4-quinolyl)oxyphenyl)-N′-(4-methoxyphenyl)urea

N-(4-(6-Cyano-7-hydroxy-4-quinolyl)oxyphenyl)-N′-(4-methoxyphenyl)urea(200 mg), potassium carbonate (65 mg) and 1-bromo-4-chlorobutane (81 μl)were suspended in dimethylformamide (3 ml), and the suspension washeated and stirred for 1 hour and 50 minutes. The reaction solution waspoured into saturated brine and extracted with ethyl acetate. Afterdrying the organic layer over magnesium sulfate, it was passed throughNH silica (Fuji Silysia Chemical) and washed in ethyl acetate, and thefiltrate was concentrated. The obtained solid was washed with ether anddried to obtain 110 mg of the title compound.

¹H-NMR (DMSO-d₆) δ (ppm): 1.96-2.00 (4H, m), 3.72 (3H, s), 3.77-3.80(2H, m), 4.33-4.37 (2H, m), 6.53 (1H, d, J=5.2 Hz), 6.88 (2H, d, J=8.8Hz), 7.23 (2H, d, J=8.8 Hz), 7.38 (2H, d, J=8.8 Hz), 7.60 (2H, d, J=8.8Hz), 7.62 (1H, s), 8.65 (1H, brs), 8.73 (1H, d, J=5.2 HZ), 8.77 (1H, s),8.90 (1H, brs).

Example 94N-(4-(6-Cyano-7-(3-chloropropoxy)-4-quinolyl)oxyphenyl)-N′-(4-methoxyphenyl)urea

The title compound (310 mg) was obtained fromN-(4-(6-cyano-7-hydroxy-4-quinolyl)oxyphenyl)-N′-(4-methoxyphenyl)urea(500 mg) and 1-chloro-3-iodopropane (188 μl), by the same procedure asin Example 93.

¹H-NMR (DMSO-d₆) δ (ppm): 2.28-2.35 (2H, m), 3.72 (3H, s), 3.86-3.90(2H, m), 4.41-4.45 (2H, m), 6.54 (1H, d, J=5.2 Hz), 6.88 (2H, d, J=8.8Hz), 7.24 (2H, d, J=8.8 Hz), 7.38 (2H, d, J=8.8 Hz), 7.61 (2H, d, J=8.8Hz), 7.65 (1H, s), 8.66 (1H, brs), 8.74 (1H, d, J=5.2 HZ), 8.79 (1H, s),8.91 (1H, brs).

Example 95N-(4-(7-(Benzyloxy)-6-cyano-4-quinolyl)oxyphenyl)-N′-(3-(methylsulfonyl)phenyl)urea

After dissolving 4-(4-aminophenoxy)-7-(benzyloxy)-6-cyanoquinoline (919mg, 2.5 mmol) in dimethylsulfoxide (10 ml), phenylN-(3-(methylsulfonyl)phenyl)carbamate (801 mg, 2.75 mmol) was added andthe mixture was heated at 85° C. for 2 hours. The reaction solution wasdiluted with ethyl acetate and then washed with 1N aqueous sodiumhydroxide (10 ml), water (20 ml×2) and saturated brine (10 ml) and driedover anhydrous sodium sulfate. After filtering off the drying agent, thefiltrate was concentrated under reduced pressure and the residue wassuspended in ethyl acetate (30 ml), after which hexane (30 ml) wasadded, sonication was performed and the precipitated crystals werefiltered out and dried under reduced pressure to obtain the titlecompound (1.43 g, 2.5 mmol, quantitative) as light brown crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.18 (3H, s), 5.44 (2H, s), 6.53 (1H,d, J=5.2 Hz), 7.24 (2H, d, J=8.8 Hz), 7.37 (1H, d, J=8.0 Hz), 7.44 (2H,t, J=7.2 Hz), 7.45-7.69 (8H, m), 8.16 (1H, s), 8.71 (1H, d, J=5.2 Hz),8.78 (1H, s), 9.12 (1H, s), 9.31 (1H, s).

Example 96N-(4-(7-(Benzyloxy)-6-cyano-4-quinolyl)oxyphenyl)-N′-phenylurea

The title compound (1.126 g, 2.3 mmol, 92.5%) was obtained as lightbrown crystals from 4-(4-aminophenoxy)-7-(benzyloxy)-6-cyanoquinoline(919 mg, 2.5 mmol) and phenyl isocyanate (0.298 ml, 2.75 mmol), by thesame procedure as in Example 10.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 5.45 (2H, s), 6.53 (1H, dd, J=1.6,5.2 Hz), 6.96 (1H, dd, J=6.0, 7.2 Hz), 7.23 (2H, d, J=7.6 Hz), 7.27 (2H,dd, J=7.2, 7.6 Hz), 7.37 (1H, d, J=7.2 Hz), 7.42-7.47 (4H, m), 7.54 (2H,d, J=8.0 Hz), 7.60 (2H, dd, J=1.2, 8.8 Hz), 7.70 (1H, s), 8.71 (1H, dd,J=1.6, 5.2 Hz), 8.78 (1H, d, J=1.2 Hz), 8.88 (1H, brs), 9.02 (1H, brs).

Example 97N-(4-((6-Cyano-7-hydroxy-4-quinolyl)oxy)phenyl)-N′-(3-(methylsulfonyl)phenyl)urea

After dissolvingN-(4-(7-(benzyloxy)-6-cyano-4-quinolyl)oxyphenyl)-N′-(3-(methylsulfonyl)phenyl)urea(1.43 g, 2.5 mmol) in trifluoroacetic acid (10 ml) and thioanisole (1.17ml, 10 mmol) under a nitrogen atmosphere, the solution was stirred at65° C. for 19 hours. The reaction solution was concentrated underreduced pressure, and after adding 5% aqueous sodium bicarbonate (30 ml)and ethyl acetate (50 ml) to the obtained residue and stirring, theprecipitated crystals were filtered out, washed with water and ethylacetate and dried under reduced pressure. The organic layer of thefiltrate was separated, washed with saturated brine and dried overanhydrous sodium sulfate, and then concentrated under reduced pressureto obtain a yellow crystalline residue. This was combined with theprevious crystals, suspended in ethyl acetate (40 ml) and subjected tosonication, and then the crystals were filtered out, washed with diethylether and dried at 60° C. to obtain the title compound (862 mg, 1.8mmol, 72.7%) as yellow crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.18 (3H, s), 6.43 (1H, d, J=5.2 Hz),7.22-7.25 (3H, m), 7.43 (1H, s), 7.48-7.68 (5H, m), 8.16 (1H, s), 8.63(1H, d, J=5.2 Hz), 8.67 (1H, s), 9.36 (1H, s), 9.55 (1H, s).

Example 98 Sodium4-(4-((anilinocarbonyl)amino)phenoxy)-6-cyano-7-quinolinolate

The title compound (811 mg, 1.94 mmol, 83.8%) was obtained as yellowcrystals fromN-(4-(7-(benzyloxy)-6-cyano-4-quinolyl)oxyphenyl-N′-phenylurea (1.126 g,2.31 mmol), by the same procedure as in Example 87.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 6.26 (1H, d, J=5.2 HZ), 6.96 (1H, m),7.18-7.29 (5H, m), 7.45 (2H, d, J=8.4 Hz), 7.57 (2H, d, J=8.0 Hz),8.50-8.51 (2H, m), 8.74 (1H, s), 8.86 (1H, s).

Example 99N-(4-(6-Cyano-7-(2-methoxyethoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-phenylurea

The title compound was obtained from4-(4-amino-3-fluorophenoxy)-6-cyano-7-(2-methoxyethoxy)quinoline andphenyl isocyanate, in the same manner as Example 10.

¹H-NMR (DMSO-d₆) δ (ppm): 3.38 (3H, s), 3.78-3.81 (2H, m), 4.42-4.45(2H, m), 6.64 (1H, d, J=5.2 Hz), 7.00 (1H, t, J=7.2 Hz), 7.15-7.19 (1H,m), 7.31 (2H, t, J=7.2 Hz), 7.42 (1H, dd, J=2.8 Hz, J=12 Hz), 7.48 (2H,d, J=7.2 Hz), 7.66 (1H, s), 8.28 (1H, t, J=8.8 HZ), 8.72 (1H, brs), 8.76(1H, d, J=5.2 Hz), 8.78 (1H, s), 9.15 (1H, brs).

Example 100N-(4-(6-Cyano-7-(2-methoxyethoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-(4-fluorophenyl)urea

The title compound was obtained from4-(4-amino-3-fluorophenoxy)-6-cyano-7-(2-methoxyethoxy)quinoline and4-fluoro phenyl isocyanate, in the same manner as Example 10.

¹H-NMR (DMSO-d₆) δ (ppm): 3.38 (3H, s), 3.78-3.81 (2H, m), 4.42-4.45(2H, m), 6.64 (1H, d, J=5.2 Hz), 7.12-7.18 (3H, m), 7.42 (1H, dd, J=2.8Hz, J=12 Hz), 7.46-7.51 (2H, m), 7.65 (1H, s), 8.25 (1H, t, J=9.2 Hz),8.71 (1H, brs), 8.76 (1H, d, J=5.2 HZ), 8.77 (1H, s), 9.18 (1H, brs).

Example 101N-(1H-Benzo[d]imidazol-6-yl)-N′-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)urea(Example 101-A)N-(1H-Benzo[d]imidazol-5-yl)-N′-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)urea(Example 101-B)

A mixture of the title compounds (Example 101-A) and (Example 101-B)(77.5 mg, 0.157 mmol, 71.4%) was obtained as white crystals from phenylN-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)carbamate (100mg, 0.220 mmol), by the same procedure as in Example 11.

The mixture of (Example 101-A) and (Example 101-B)

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.36 (3H, s), 3.76-3.79 (2H, m),4.40-4.43 (2H, m), 6.53 (1H, d, J=5.6 Hz), 6.99-7.62 (6H, m), 7.82(2/5H, s), 7.91 (3/5H, s), 8.08 (3/5H, s), 8.13 (2/5H, s), 8.59-8.79(5H, m), 12.26 (3/5H, s), 12.29 (2/5H, s).

Example 102N-(4-(6-Cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)-N′-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)urea

The title compound (104.2 mg, 0.204 mmol, 93.0%) was obtained as whitecrystals from phenylN-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)carbamate (100mg, 0.220 mmol), by the same procedure as in Example 11.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.36 (3H, s), 3.76-3.79 (2H, m),4.40-4.43 (2H, m), 6.52 (1H, d, J=5.2 Hz), 6.81 (2H, s), 7.22 (2H, d,J=8.0 Hz), 7.31 (1H, s), 7.58 (2H, d, J=8.0 Hz), 7.62 (1H, s), 8.53 (1H,s), 8.71-8.76 (3H, m), 10.41 (1H, s), 10.50 (1H, s).

Example 103N-(4-(6-Cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)-N′-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)urea

The title compound (101 mg, 0.197 mmol, 89.9%) was obtained as graycrystals from phenylN-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)carbamate (100mg, 0.220 mmol), by the same procedure as in Example 11.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.37 (3H, s), 3.76-3.39 (2H, m),4.40-4.43 (2H, m), 6.52 (1H, d, J=5.2 Hz), 6.91 (1H, dd, J=2.0, 8.8 Hz),7.17 (1H, d, J=8.4 Hz), 7.24 (2H, d, J=8.8 Hz), 7.48 (1H, s), 7.59 (2H,d, J=8.8 Hz), 7.62 (1H, s), 8.71-8.77 (3H, m), 8.81 (1H, s), 11.53 (1H,s).

Example 104N-(4-(6-Cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)-N′-(2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)urea

The title compound (111 mg, 0.217 mmol, 98.8%) was obtained as graycrystals from phenylN-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)carbamate (100mg, 0.220 mmol), by the same procedure as in Example 11.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.37 (3H, s), 3.76-3.79 (2H, m),4.40-4.43 (2H, m), 6.52 (1H, d, J=5.2 Hz), 6.99 (1H, d, J=8.4 Hz), 7.07(1H, dd, J=2.0, 8.4 Hz), 7.24 (2H, d, J=8.8 Hz), 7.56-7.63 (4H, m), 8.72(1H, d, J=5.2 Hz), 8.74 (1H, s), 8.76 (1H, s), 8.82 (1H, s), 11.46 (1H,s).

Example 105N-(4-(6-Cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)-N′-(2-oxo-2,3-dihydro-1H-5-indolyl)urea

The title compound (69 mg, 0.135 mmol, 61.7%) was obtained as graycrystals from phenylN-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)carbamate (100mg, 0.220 mmol), by the same procedure as in Example 11.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.36 (3H, s), 3.45 (2H, s), 3.76-3.79(2H, s), 4.40-4.43 (2H, m), 6.51 (1H, d, J=5.2 Hz), 6.72 (1H, d, J=8.4Hz), 7.17 (1H, dd, J=2.0, 8.4 Hz), 7.22 (2H, d, J=8.8 Hz), 7.37 (1H, s),7.58 (2H, d, J=8.8 Hz), 7.62 (1H, s), 8.49 (1H, s), 8.71 (1H, d, J=5.2Hz), 8.74 (1H, s), 8.75 (1H, s), 10.23 (1H, s).

Example 106N-(4-(6-Cyano-7-(3-hydroxypropoxy)-4-quinolyl)oxyphenyl-N′-(4-fluorophenyl)urea

The title compound (64 mg, 0.135 mmol, 54.2%) was obtained as lightyellow crystals from sodium6-cyano-4-(4-((4-fluoroanilino)carbonyl)aminophenoxy)-7-quinolinolate(109 mg, 0.250 mmol), by the same procedure as in Example 7.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.97 (2H, t, J=6.0 Hz), 3.63 (2H, m),4.34 (2H, t, J=6.0 Hz), 4.63 (1H, t, J=5.2 Hz), 6.51 (1H, d, J=5.2 Hz),7.11 (2H, t, J=8.8 Hz), 7.23 (2H, d, J=8.8 Hz), 7.44-7.47 (2H, m),7.57-7.60 (3H, m), 8.70-8.75 (3H, m), 8.82 (1H, s).

Example 107N-(4-(6-Cyano-7-(3-(methylsulfanyl)propoxy)-4-quinolyloxy)phenyl)-N′-(4-fluorophenyl)urea

The title compound (37 mg, 0.074 mmol, 29.5%) was obtained as lightbrown crystals from sodium6-cyano-4-(4-((4-fluoroanilino)carbonyl)aminophenoxy)-7-quinolinolate(109 mg, 0.250 mmol), by the same procedure as in Example 7.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.08-2.12 (5H, m), 2.69 (2H, t, J=7.2Hz), 4.36 (2H, t, J=6.0 Hz), 6.52 (1H, d, J=5.2 Hz), 7.11 (2H, t, J=8.8Hz), 7.23 (2H, d, J=8.8 Hz), 7.44-7.48 (2H, m), 7.57-7.60 (3H, m),8.71-8.76 (3H, m), 8.82 (1H, s).

Example 108N-(4-(6-Cyano-7-(3-(methylsulfonyl)propoxy)-4-quinolyloxy)phenyl)-N′-(4-fluorophenyl)urea

The title compound (70 mg, 0.131 mmol, 52.4%) was obtained as lightbrown crystals from sodium6-cyano-4-(4-((4-fluoroanilino)carbonyl)aminophenoxy)-7-quinolinolate(109 mg, 0.250 mmol), by the same procedure as in Example 7.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.27 (2H, m), 3.04 (3H, s), 3.21-3.37(2H, m), 4.41 (2H, t, J=6.4 Hz), 6.53 (1H, d, J=5.2 Hz), 7.11 (2H, t,J=8.8 Hz), 7.23 (2H, d, J=8.8 Hz), 7.44-7.48 (2H, m), 7.57-7.61 (3H, m),8.71-8.73 (2H, m), 8.77 (1H, s), 8.82 (1H, s).

Example 109N-(4-(6-Cyano-7-(3-(2-oxotetrahydro-1H-1-pyrrolyl)propoxy)-4-quinolyloxy)phenyl)-N′-(4-fluorophenyl)urea

The title compound (11.2 mg, 0.021 mmol, 8.3%) was obtained as lightyellow crystals from sodium6-cyano-4-(4-((4-fluoroanilino)carbonyl)aminophenoxy)-7-quinolinolate(109 mg, 0.250 mmol), by the same procedure as in Example 7.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.93 (2H, m), 2.03 (2H, t, J=6.0 Hz),2.19 (2H, t, J=8.0 Hz), 3.37-3.42 (4H, m), 4.27 (2H, t, J=6.0 Hz), 6.51(1H, d, J=5.2 Hz), 7.11 (2H, t, J=8.8 Hz), 7.23 (2H, d, J=8.8 Hz),7.44-7.48 (2H, m), 7.55 (1H, s), 7.58 (2H, d, J=8.8 Hz), 8.70-8.73 (2H,m), 8.75 (1H, s), 8.82 (1H, s).

Example 110N-(4-(6-Cyano-7-(3-(1,3-dioxo-2,3-dihydro-1H-2-isoindolyl)propoxy)-4-quinolyloxy)phenyl)-N′-(4-fluorophenyl)urea

The title compound (416 mg, 0.692 mmol, 69.2%) was obtained as lightyellow crystals from sodium6-cyano-4-(4-((4-fluoroanilino)carbonyl)aminophenoxy)-7-quinolinolate(436 mg, 1.00 mmol), by the same procedure as in Example 7.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.17 (2H, t, J=5.6 Hz), 3.84 (2H, t,J=6.4 Hz), 4.32 (2H, t, J=6.0 Hz), 6.51 (1H, d, J=5.2 Hz), 7.11 (2H, t,J=8.8 Hz), 7.23 (2H, d, J=9.2 Hz), 7.44-7.48 (2H, m), 7.52 (1H, s), 7.58(2H, d, J=8.8 Hz), 7.78-7.84 (4H, m), 8.69-8.73 (3H, m), 8.82 (1H, s).

Example 111N-(3-(6-Cyano-4-(3-fluoro-4-((4-fluoroanilino)carbonyl)aminophenoxy)-7-quinolyl)oxypropyl)methanesulfonamide

The title compound (73 mg, 0.129 mmol, 51.3%) was obtained as lightbrown crystals from sodium6-cyano-4-(3-fluoro-4-((4-fluoroanilino)carbonyl)aminophenoxy)-7-quinolinolate(114 mg, 0.25 mmol), by the same procedure as in Example 7.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.02 (2H, t, J=6.4 Hz), 2.91 (3H, s),3.20 (2H, q, J=6.4 Hz), 4.34 (2H, t, J=6.4 Hz), 6.62 (1H, d, J=5.2 Hz),7.12-7.38 (4H, m), 7.40 (1H, dd, J=2.8, 11.6 Hz), 7.44-7.48 (2H, m),7.61 (1H, s), 8.24 (1H, t, J=9.2 Hz), 8.62 (1H, d, J=2.0 Hz), 8.74 (1H,s), 8.75 (1H, s), 9.09 (1H, s).

Example 1124-(4-((4-Fluoroanilino)carbonyl)aminophenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxamide

TheN-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)-N′-(4-fluorophenyl)urea(360 mg, 0.762 mmol) obtained in Example 10 was dissolved indimethylsulfoxide (4.5 ml), and then 5N aqueous sodium hydroxide (1.5ml) was added and the mixture was heated at 80° C. while stirring for 60minutes. The reaction solution was cooled in an ice water bath, 2Nhydrochloric acid (3.75 ml) was added for neutralization, and then themixture was diluted with water (21 ml) and the precipitated crudecrystals were filtered out. These were suspended in ethanol (20 ml) andsubjected to sonication, and upon filtering out the crystals they weredried under reduced pressure to obtain the title compound (214 mg, 0.436mmol, 57.3%) as gray crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.34 (3H, s), 3.78-3.81 (2H, m),4.38-4.41 (2H, m), 6.46 (1H, d, J=5.6 Hz), 7.11 (2H, d, J=8.8 Hz), 7.23(2H, d, J=8.4 Hz), 7.46 (2H, m), 7.54 (1H, s), 7.58 (2H, d, J=8.8 Hz),7.80 (1H, s), 7.82 (1H, s), 8.64 (1H, d, J=5.6 Hz), 8.75 (1H, s), 8.78(1H, s), 8.83 (1H, s).

Example 1137-(2-Methoxyethoxy)-4-(4-((1,3-thiazol-2-ylamino)carbonyl)aminophenoxy)-6-quinolinecarboxamide

The title compound (181 mg, 0.377 mmol, 42.6%) was obtained as graycrystals from theN-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)-N′-(1,3-thiazol-2-yl)urea(409 mg, 0.886 mmol) obtained in Example 12, by the same procedure as inExample 112.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.35 (3H, s), 3.78-3.81 (2H, m),4.39-4.42 (2H, m), 6.47 (1H, d, J=5.2 Hz), 7.11 (1H, brs), 7.26 (2H, d,J=8.8 Hz), 7.37 (1H, d, J=3.2 Hz), 7.55 (1H, s), 7.62 (2H, d, J=8.8 Hz),7.80 (1H, s), 7.82 (1H, s), 8.65 (1H, d, J=5.2 Hz), 8.78 (1H, s), 9.10(1H, s).

Example 1144-4-((Anilinocarbonyl)amino)-3-fluorophenoxy-7-(2-methoxyethoxy)-6-quinolinecarboxamide

The title compound (21 mg, 0.043 mmol, 19.1%) was obtained as browncrystals from theN-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-phenylurea(106 mg, 0.224 mmol) obtained in Example 99, by the same procedure as inExample 112. ¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.35 (3H, s), 3.78-3.81(2H, m), 4.39-4.42 (2H, m), 6.55 (1H, d, J=5.2 Hz), 6.98 (1H, t, J=7.6Hz), 7.13 (1H, d, J=8.4 Hz), 7.29 (2H, t, J=7.6 Hz), 7.39 (1H, dd,J=2.4, 12.0 Hz), 7.45 (2H, d, J=8.4 Hz), 7.56 (1H, s), 7.82 (2H, brs),8.25 (1H, m), 8.63 (1H, s), 8.67 (1H, d, J=5.2 Hz), 8.76 (1H, s), 9.06(1H, s).

Example 1154-(4-((4-Fluoroanilino)carbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (201 mg, 0.450 mmol, 49.2%) was obtained as graycrystals from theN-(4-(6-cyano-7-methoxy-4-quinolyl)oxyphenyl)-N′-(4-fluorophenyl)urea(391 mg, 0.913 mmol) obtained in Example 39, by the same procedure as inExample 112.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 4.02 (3H, s), 6.53 (1H, d, J=5.2 Hz),7.11 (2H, t, J=8.8 Hz), 7.24 (2H, d, J=8.8 Hz), 7.44-7.48 (2H, m), 7.51(1H, s), 7.59 (2H, d, J=8.8 Hz), 7.75 (1H, s), 7.87 (1H, s), 8.68-8.70(2H, m), 8.85 (1H, s), 8.95 (1H, s).

Example 1164-(4-((Cyclopropylamino)carbonyl)aminophenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxamide

The title compound (71 mg, 0.163 mmol, 45.4%) was obtained as lightbrown crystals from theN-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)-N′-cyclopropylurea(150 mg, 0.358 mmol) obtained in Example 23, by the same procedure as inExample 112.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.40-0.44 (2H, m), 0.62-0.66 (2H, m),2.43-2.48 (1H, m), 3.36 (3H, s), 3.80-3.83 (2H, m), 4.40-4.43 (2H, m),6.43-6.46 (2H, m), 7.18 (2H, d, J=8.8 Hz), 7.53-7.67 (3H, m), 7.81 (1H,s), 7.83 (1H, s), 8.46 (1H, s), 8.65 (1H, d, J=5.6 Hz), 8.79 (1H, s).

Example 117N-4-((6-Cyano-7-methoxy-4-quinolyl)oxy)phenyl)-N′-(1,3-thiazol-2-yl)urea

The title compound (390 mg, 0.934 mmol, 93.4%) was obtained as whitecrystals from 4-(4-aminophenoxy)-6-cyano-7-methoxyquinoline (291 mg, 1.0mmol) and 2-phenoxycarbamoylamino-1,3-thiazole (264 mg, 1.2 mmol), bythe same procedure as in Example 36.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 4.05 (3H, s), 6.52 (1H, d, J=5.2 Hz),7.11 (1H, br), 7.27 (2H, d, J=8.8 Hz), 7.37 (1H, d, J=3.2 Hz), 7.59 (1H,s), 7.62 (2H, d, J=8.8 Hz), 8.72 (1H, d, J=5.2 Hz), 8.77 (1H, s), 9.12(1H, s).

Example 1187-Methoxy-4-(4-((1,3-thiazol-2-ylamino)carbonyl)aminophenoxy)-6-quinolinecarboxamide

The title compound (195 mg, 0.448 mmol, 52.8%) was obtained as graycrystals from theN-4-((6-cyano-7-methoxy-4-quinolyl)oxy)phenyl-N′-(1,3-thiazol-2-yl)urea(354 mg, 0.848 mmol) obtained in Example 117, by the same procedure asin Example 112.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 4.02 (3H, s), 6.47 (1H, d, J=5.2 Hz),7.10 (1H, br), 7.25 (2H, d, J=8.8 Hz), 7.36 (1H, d, J=3.6 Hz), 7.50 (1H,s), 7.62 (2H, d, J=8.8 Hz), 7.73 (1H, s), 7.85 (1H, s), 8.64 (1H, d,J=5.2 Hz), 8.67 (1H, s), 9.45 (1H, s).

Example 1194-(4-((2,4-Difluoroanilino)carbonyl)amino-3-fluorophenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (36 mg, 0.448 mmol, 29.4%) was obtained as light pinkcrystals from theN-(4-(6-cyano-7-methoxy-4-quinolyl)oxy-2-fluorophenyl)-N′-(2,4-difluorophenyl)urea(118 mg, 0.254 mmol) obtained in Example 61, by the same procedure as inExample 112.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 4.02 (3H, s), 6.56 (1H, d, J=5.2 Hz),7.06 (1H, m), 7.12 (1H, m), 7.33 (1H, m), 7.39 (1H, dd, J=2.8, 11.6 Hz),7.51 (1H, s), 7.73 (1H, s), 7.84 (1H, s), 8.11 (1H, m), 8.25 (1H, t,J=9.2 Hz), 8.65 (1H, s), 8.66 (1H, d, J=5.2 Hz), 8.99 (1H, s), 9.06 (1H,s).

Example 120N-4-((6-Cyano-7-methoxy-4-quinolyl)oxy)phenyl-N′-cyclopropylurea

The title compound (293 mg, 0.783 mmol, 59.8%) was obtained as whitecrystals from 4-(4-aminophenoxy)-6-cyano-7-methoxyquinoline (381 mg,1.308 mmol), by the same procedure as in Example 36.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.40-0.44 (2H, m), 0.62-0.67 (2H, m),2.53-2.58 (1H, m), 4.07 (3H, m), 6.44 (1H, d, J=2.0 Hz), 6.51 (1H, d,J=5.6 Hz), 7.19 (2H, d, J=8.8 Hz), 7.56 (2H, d, J=8.8 Hz), 7.60 (1H, s),8.48 (1H, s), 8.73 (1H, d, J=5.6 Hz), 8.77 (1H, s).

Example 1214-(4-((Cyclopropylamino)carbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (79 mg, 0.201 mmol, 26.9%) was obtained as graycrystals from theN-4-((6-cyano-7-methoxy-4-quinolyl)oxy)phenyl-N′-cyclopropylurea (279mg, 0.745 mmol) obtained in Example 120, by the same procedure as inExample 112.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.40-0.43 (2H, m), 0.62-0.64 (2H, m),2.42-2.45 (1H, m), 4.02 (3H, s), 6.42-6.44 (2H, m), 7.16 (2H, d, J=8.0Hz), 7.49 (1H, s), 7.53 (2H, d, J=8.0 Hz), 7.72 (1H, s), 7.84 (1H, s),8.45 (1H, s), 8.63 (1H, d, J=5.6 Hz), 8.67 (1H, s).

Example 122N-(4-(5,6-Dimethyl-4-7H-pyrrolo[2,3-d]pyrimidyl)oxyphenyl)-N′-(4-fluorophenyl)urea

4-(4-Aminophenoxy)-5,6-dimethyl-7H-pyrrolo[2,3-d]-pyrimidine wasdissolved in toluene (16 mg) (0.8 ml) and acetonitrile (0.5 ml) underreflux, and then 4-fluorophenylisocyanate (7.9 μM) was added. Themixture was stirred for 1 hour and returned to room temperature, andthen the reaction system was concentrated, diethyl ether was added tothe residue, and the resulting crystals were filtered out. The crystalswere washed with diethyl ether to obtain the title compound (5 mg).

MS m/z 392 (M+H)

¹H-NMR (DMSO-d₆) δ (ppm): 2.29 (3H, s), 2.31 (3H, s), 7.00-7.16 (4H, m),7.38-7.50 (4H, m), 8.10 (1H, s), 8.50 (2H, s), 11.75 (1H, s)

The intermediates were synthesized in the following manner.

Production Example 122-14-(Nitrophenoxy)-5,6-dimethyl-7H-pyrrolo[2,3-d]-pyrimidine

After adding para-nitrophenol (121 mg), potassium carbonate (133 mg) anddimethylformamide (1 ml) to the4-chloro-5,6-7H-pyrrolo[2,3-d]-pyrimidine (88 mg) described in Journalof Medicinal Chemistry, 1996, Vol. 39, No. 12, 2285-2292, the mixturewas stirred at 135-140° C. for 72 hours. This was returned to roomtemperature, water was added, extraction was performed with atetrahydrofuran and ethyl acetate mixed solution, and then the organiclayer was washed with saturated brine, dried over anhydrous sodiumsulfate and concentrated to dryness. The obtained crystals were washedwith diethyl ether to obtain the title compound (90 mg).

MS m/z 285 (M+H)

¹H-NMR (DMSO-d₆) δ (ppm): 2.28 (3H, s), 2.32 (3H, s), 7.50 (2H, d, J=9.5Hz), 8.20 (1H, s), 8.30 (2H, d, J=9.5 Hz), 11.98 (1H, s)

Production Example 122-24-(Aminophenoxy)-5,6-dimethyl-7H-pyrrolo[2,3-d]-pyrimidine

After adding iron powder (0.1 g), ammonium chloride (0.2 g), ethanol (4ml) and water (1 ml) to the4-(nitrophenoxy)-5,6-dimethyl-7H-pyrrolo[2,3-d]-pyrimidine (80 mg)synthesized by the intermediate synthesis method described above, themixture was stirred at 75-82° C. for 1.5 hours. After returning thereaction system to room temperature and adding tetrahydrofuran (3 ml)and ethyl acetate (3 ml), the mixture was filtered with celite, thefiltrate was subjected to liquid separation, and the organic layer waswashed with water and saturated brine in that order, dried over sodiumsulfate, concentrated to dryness under reduced pressure and washed withdiethyl ether to obtain the title compound (22 mg).

MS m/z 255 (M+H)

¹H-NMR (DMSO-d₆) δ (ppm): 2.27 (3H, s), 2.29 (3H, s), 4.90-5.00 (2H, m),6.52-6.88 (4H, m), 8.06 (1H, s), 11.66 (1H, s)

Example 1234-(4-(3,4-Dihydroquinazolin-2-one-3-yl)phenyloxy)-6,7-dimethoxyquinoline

6,7-Dimethoxy-4-(4-(2-aminophenyl)methylaminophenyloxy)quinoline (40 mg,0.0996 mmol) was dissolved in dimethylformamide (0.5 ml),1,1′-carbonyldiimidazole (19 mg, 0.1196 mmol) was added, and the mixturewas stirred at 70° C. for 8 hours. After cooling to room temperature,the reaction solution was diluted with tetrahydrofuran, water was added,and the mixture was extracted with ethyl acetate, washed with saturatedbrine and dried over anhydrous magnesium sulfate, after which thesolvent was distilled off under reduced pressure. The residue waspurified with a silica gel column (ethyl acetate-methanol system) andrecrystallized with hexane-diethyl ether to obtain the title compound (3mg, 0.0070 mmol, 7.05%) as colorless crystals.

¹H-NMR (CDCl₃) δ (ppm): 4.06 (6H, s), 4.89 (2H, s), 6.57 (1H, d, J=5.2Hz), 6.77 (1H, d, J=7.6 Hz), 6.87 (1H, brs), 7.03 (1H, t, J=7.6 Hz),7.14 (1H, d, J=7.6 Hz), 7.23 (3H, m, covered by CDCl₃), 7.44 (1H, s),7.48 (2H, d, J=8.8 Hz), 7.55 (1H, s), 8.52 (1H, d, J=5.2 Hz).

The intermediates were synthesized in the following manner.

Production Example 123-16,7-Dimethoxy-4-(4-(2-nitrophenylmethylimino)phenyloxy)quinoline

6,7-Dimethoxy-4-(4-aminophenyloxy)quinoline (500 mg, 1.6873 mmol) wasdissolved in tetrahydrofuran (64 ml), and after adding2-nitrobenzaldehyde (320 mg, 2.1091 mmol) and acetic acid (0.58 ml),sodium triacetoxyborohydride (720 mg, 3.3746 mmol) was further added andthe mixture was stirred at room temperature for 11 hours and 30 minutes.Water and saturated sodium bicarbonate were added, the mixture wasextracted with ethyl acetate, washed with saturated brine and dried overanhydrous magnesium sulfate, and the solvent was distilled off underreduced pressure. The obtained crystals were washed with hexane-diethylether, filtered out, washed with hexane and dried by aspiration at roomtemperature to obtain the title compound (453 mg) as light yellowcrystals.

¹H-NMR (CDCl₃) δ (ppm): 4.06 (6H, s), 6.54 (1H, d, J=5.2 Hz), 7.25 (2H,d, J=8.4 Hz), 7.40 (2H, d, J=8.4 Hz), 7.44 (1H, s), 7.57 (1H, s), 7.65(1H, dd, J=7.6, 8.0 Hz), 7.77 (1H, dd, J=7.6, 7.6 Hz), 8.10 (1H, d,J=8.0 Hz), 8.33 (1H, d, J=7.6 Hz), 8.51 (1H, d, J=5.2 Hz), 9.01 (1H, s).

Production Example 123-26,7-Dimethoxy-4-(4-(2-nitrophenylmethylamino)phenyloxy)quinoline

After adding tetrahydrofuran (2 ml), ethanol (2 ml) and chloroform (1ml) to 6,7-dimethoxy-4-(4-(2-nitrophenylmethyl-imino)phenyloxy)quinoline(200 mg, 0.4657 mmol) and heating the mixture to complete dissolution,sodium borohydride (35 mg, 0.9314 mmol) was added and the mixture washeated to reflux for 1 hour and 30 minutes. After cooling to roomtemperature, water was added, the mixture was extracted with ethylacetate, washed with saturated brine and dried over anhydrous magnesiumsulfate, and the solvent was distilled off under reduced pressure. Theresidue was purified with an NH silica gel column (hexane-ethyl acetatesystem) to obtain the title compound (151 mg, 0.3500 mmol, 75.15%) as ayellow oil.

¹H-NMR (CDCl₃) δ (ppm): 4.04 (6H, s), 4.46 (1H, brs), 4.76 (2H, d, J=4.8Hz), 6.42 (1H, d, J=5.2 Hz), 7.64 (2H, d, J=8.8 Hz), 6.99 (2H, d, J=8.8Hz), 7.40 (1H, s), 7.47 (1H, dd, J=7.2, 7.2 Hz), 7.57 (1H, s), 7.62 (1H,dd, J=7.2, 7.6 Hz), 7.71 (1H, d, J=7.6 Hz), 8.10 (1H, d, J=7.2 Hz), 8.45(1H, d, J=5.2 Hz).

Production Example 123-36,7-Dimethoxy-4-(4-(2-aminophenylmethylamino)phenyloxy)quinoline

6,7-Dimethoxy-4-(4-(2-nitrophenylmethylamino)phenyloxy)quinoline (150mg, 0.35 mmol) was dissolved in ethanol (2.8 ml) and water (0.7 ml), andthen iron powder (78 mg, 1.4 mmol) and ammonium chloride (150 mg, 2.8mmol) were added and the mixture was heated to reflux for 1 hour. Aftercooling to room temperature, the reaction solution was diluted withtetrahydrofuran and water, and the insoluble portion was filtered off.The filtrate was distilled off under reduced pressure, and then theresidue was purified with a silica gel column (ethyl acetate system),the obtained amorphous substance was solidified with hexane and ethylacetate, and the obtained crystals were washed with hexane-ethylacetate, filtered out, washed with hexane and dried by aspiration atroom temperature to obtain the title compound (80 mg, 0.1993 mmol,56.93%) as milky white crystals.

¹H-NMR (CDCl₃) δ (ppm): 3.78 (1H, brs), 4.05 (3H, s), 4.06 (3H, s), 4.15(2H, brs), 4.26 (2H, s), 6.44 (1H, d, J=5.2 Hz), 6.74-6.81 (4H, m), 7.06(2H, d, J=8.8 Hz), 7.16-7.22 (2H, m), 7.42 (1H, s), 7.60 (1H, s), 8.46(1H, d, J=5.2 Hz).

Example 124N-(4-(2-Phenylpyridin-4-yl)oxyphenyl)-N′-(4-fluorophenyl)urea

4-(2-Phenylpyridin-4-yl)oxyaniline (110 mg, 0.42 mM) was added to ethylacetate (10 ml), and then parafluorophenyl isocyanate (0.56 ml, 4.9 mM)was added while stirring, which was continued for 30 minutes. Afteradding n-hexane (20 ml) to the reaction solution, the solvent waspartially distilled off under reduced pressure and the precipitatingsolid was filtered out to obtain the target substance (98 mg) as a graysolid.

¹H-NMR (DMSO-d₆) δ (ppm): 6.81 (1H, dd, J=5.6 Hz, J=2.4 Hz), 7.10-7.20(4H, m), 7.42-7.52 (6H, m), 7.57 (2H, d, J=8.8 Hz) 8.01 (2H, d, J=8.4Hz), 8.53 (1H, d, J=5.6 Hz), 8.74 (1H, s), 8.80 (1H, s).

The starting material and intermediate were synthesized in the followingmanner.

Production Example 124-1 4-(2-Phenylpyridin-4-yl)oxyaniline

4-Chloro-2-phenylpyridine 1.0 g (5.5 mM), paranitrophenol (1.68 g, 12mM), Hunig's base (diisopropylethylamine, 5 ml) and 1-methylpyrrolidone(10 ml) were stirred at 160° C. for 20 hours. Water was added,extraction was performed with ethyl acetate, and the organic layer waswashed 5 times with water. The solvent was distilled off under reducedpressure and the residue was purified by silica gel chromatography(hexane:ethyl acetate=4:1) to obtain 490 mg of4-(4-nitrophenoxy)-2-phenylpyridine as a light yellow solid.

¹H-NMR (DMSO-d₆) δ (ppm): 7.08-7.14 (1H, m), 7.40-7.53 (5H, m), 7.74(1H, s), 8.07-8.13 (2H, m) 8.34 (2H, d, J=8.8 Hz), 8.68 (1H, dd, J=5.6Hz, J=1.2 Hz).

4-(4-nitrophenoxy)-2-phenylpyridine (490 mg), iron powder (1 g),ammonium chloride (2 g), ethanol (10 ml), dimethylformamide (10 ml) andwater (5 ml) were stirred at 100° C. for 10 minutes. The mixture wasfiltered with celite, water was added to the filtrate, and extractionwas performed with ethyl acetate. The organic layer was washed 5 timeswith water, and then the solvent was distilled off under reducedpressure to obtain 4-(2-phenylpyridin-4-yl)oxyaniline (460 mg) as abrown oil.

¹H-NMR (DMSO-d₆) δ (ppm): 5.12-5.16 (2H, m), 6.65 (2H, d, J=8.8 Hz),6.74 (1H, dd, J=5.6 Hz, J=2.4 Hz), 6.89 (2H, d, J=8.8 Hz), 7.38 (1H, d,J=2.4 Hz), 7.40-7.52 (3H, m), 7.98 (2H, d, J=8.0 Hz), 8.48 (1H, d, J=5.6Hz).

Example 125N-(4-(3-Phenylpyridin-4-yl)oxyphenyl)-N′-(4-fluorophenyl)urea

Ethyl acetate (10 ml) was added to 4-(3-phenylpyridin-4-yl)oxyaniline(84 mg, 0.32 mM), and then parafluorophenyl isocyanate (0.54 ml, 4.7 mM)was added while stirring, which was continued for 40 minutes. Afteradding NH type silica gel to the reaction solution, the solvent wasdistilled off under reduced pressure to adsorb the reaction product ontothe silica gel. The silica gel was charged into a dry column packed withNH type silica gel, for column purification (chloroform:methanol=10:1).After adding ethyl acetate and n-hexane to the obtained residue, thesolvent was distilled off under reduced pressure to obtain the targetcompound (82 mg) as a light yellow amorphous substance.

¹H-NMR (DMSO-d₆) δ (ppm): 6.69 (1H, dd, J=5.6 Hz, J=1.6 Hz), 7.06-7.15(4H, m), 7.37-7.54 (7H, m), 7.64 (2H, d, J=7.6 Hz), 8.38 (1H, dd, J=5.6Hz, J=1.6 Hz), 8.51 (1H, d, J=1.6 Hz), 8.70 (1H, s), 8.75 (1H, s).

The starting material and intermediate were synthesized in the followingmanner.

Production Example 125-1 4-(3-Phenylpyridin-4-yl)oxyaniline

4-Chloro-3-phenylpyridine (200 mg, 1.06 mM), paranitrophenol (440 mg,3.18 mM), Hunig's base (isoPr₂EtN, diisopropylethylamine, 1 ml) and1-methylpyrrolidone (2 ml) were stirred at 160° C. for 2 hours. Waterwas added, extraction was performed with ethyl acetate, and the solventwas distilled off under reduced pressure. The residue was purified bysilica gel chromatography (hexane:ethyl acetate=4:1, and then 2:1) toobtain 4-(4-nitrophenoxy)-3-phenylpyridine (150 mg) as a light yellowoil.

¹H-NMR(CDCl3) δ (ppm): 6.98 (1H, d, J=5.6 Hz), 7.12 (2H, d, J=9.2 Hz),7.37-7.48 (3H, m), 7.50-7.56 (2H, m) 8.24 (2H, d, J=9.3 Hz), 8.55 (1H,d, J=5.6 Hz), 8.71 (1H, s).

4-(4-Nitrophenoxy)-3-phenylpyridine (150 mg), iron powder (300 mg),ammonium chloride (600 mg), ethanol (5 ml), dimethylformamide (5 ml) andwater (2.5 ml) were stirred at 100° C. for 15 minutes. The mixture wasfiltered with celite, water was added to the filtrate, and extractionwas performed with ethyl acetate. The organic layer was washed 5 timeswith water, and then the solvent was distilled off under reducedpressure to obtain 4-(3-phenylpyridin-4-yl)oxyaniline (84 mg) as ayellow oil.

¹H-NMR(CDCl₃) δ (ppm): 6.65-6.74 (3H, m), 6.88 (2H, d, J=8.8 Hz),7.36-7.50 (3H, m), 7.64 (2H, d, J=8.8 Hz), 8.34 (1H, dd, J=5.6 Hz, J=0.8Hz), 8.54 (1H, s).

Example 126N-(3-(6,7-Dimethoxyquinolin-4-yl)oxypropyl)-N′-(4-fluorophenyl)urea

6,7-Dimethoxy-4-(3-aminopropoxy)quinoline 150 mg (0.57 mM) and ethylacetate (20 ml) were stirred at room temperature, and then4-fluorophenyl isocyanate (0.078 ml, 0.68 mM) was added and the mixturewas further stirred for 15 minutes. The precipitated solid was filteredout to obtain the target substance (92 mg) as a white solid.

¹H-NMR (DMSO-d₆) δ (ppm): 2.03 (2H, tt, J=6.0 Hz, J=6.0 Hz), 3.36 (2H,t, J=6.0 Hz), 3.89 (3H, s), 3.91 (3H, s), 4.27 (2H, t, J=6.0 Hz), 6.29(1H, t, J=6.0 Hz), 6.88 (1H, d, J=5.2 Hz), 7.00-7.07 (2H, m), 7.31 (1H,s), 7.34-7.41 (3H, m), 8.47 (1H, s), 8.51 (1H, d, J=5.2 Hz).

The starting material and intermediate were synthesized in the followingmanner.

Production Example 126-1 6,7-Dimethoxy-4-(3-aminopropoxy)quinoline

6,7-Dimethoxy-4-hydroxyquinoline (4.0 g, 19.5 mM),N-(3-bromopropyl)phthalimide (5.8 g, 21.5 mM), potassium carbonate (5.4g, 39 mM) and DMF dimethylformamide (20 ml) were stirred at 60° C. for1.5 hours. Water, ethyl acetate and tetrahydrofuran were added to thereaction solution for extraction. The solid which precipitated afterstanding for a period was filtered out to obtainN-(3-(6,7-dimethoxyquinolin-4-yloxy)propyl)phthalimide (1.1 g).

¹H-NMR (DMSO-d₆) δ (ppm): 2.22 (2H, tt, J=6.0 Hz, J=6.0 Hz), 3.82 (3H,s), 3.86 (2H, t, J=6.0 Hz), 3.90 (3H, s), 4.29 (2H, t, J=6.0 Hz), 6.82(1H, d, J=5.2 Hz), 7.27 (1H, s), 7.31 (1H, s), 7.77-7.84 (4H, m), 8.49(1H, d, J=5.2 Hz).

N-(3-(6,7-Dimethoxyquinolin-4-yloxy)propyl)phthalimide (600 mg, 1.53mM), hydrazine monohydrate (300 mg, 6.12 mM), ethanol (5 ml), methanol(5 ml) and tetrahydrofuran (5 ml) were stirred for 2 hours under reflux.The solvent was distilled off under reduced pressure, and the residuewas purified by silica gel chromatography (Fuji Silysia NH Type SilicaGel, chloroform:methanol=20:1) to obtain the target substance (150 mg)as a brown oil.

¹H-NMR (DMSO-d₆) δ (ppm): 1.93 (2H, tt, J=6.0 Hz, J=6.0 Hz), 2.77 (2H,t, J=6.0 Hz), 3.88 (3H, s), 3.91 (3H, s), 4.29 (2H, t, J=6.0 Hz), 6.89(1H, d, J=5.2 Hz), 7.31 (1H, s), 7.34 (1H, s), 8.51 (1H, d, J=5.2 Hz).

Example 127N-(4-(6-Cyano-7-((1-methylpiperidin-3-yl)methoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-(4-fluorophenyl)urea

After dissolving6-cyano-4-(4-(4-fluoroanilinocarbonyl)amino-3-fluorophenoxy)quinolin-7-olsodium salt (222 mg), potassium carbonate (162 mg) and3-chloromethyl-1-methylpiperidine hydrochloride (86 mg) indimethylformamide (1.7 ml) and stirring the mixture overnight at 70-80°C., water was added, and extraction was performed with a tetrahydrofuranand ethyl acetate mixed solvent prior to concentration under reducedpressure and purification of the residue with NH Silica (Fuji SilysiaChemical). The obtained solid was washed with ether and dried to obtainthe title compound (10 mg).

MS Spectrum: 544 (M+1)

1H-NMR Spectrum: (DMSOd₆) 1.30-2.70 (12H, m), 4.17 (2H, d, J=6.7 Hz),6.61 (1H, d, J=5.0 Hz), 7.06-7.18 (3H, m), 7.36-7.50 (3H, m), 7.60 (1H,s,), 8.20-8.28 (1H, m), 8.63 (1H, s,), 8.74 (1H, d, J=5.0 Hz), 8.75 (1H,s,), 9.10 (1H, s,)

Example 128N-(3-(5,6-Dimethyl-4-7H-pyrrolo[2,3-d]pyrimidyl)oxyphenyl)-N′-(4-fluorophenyl)urea

After dissolving4-amino(3-aminophenoxy)-5,6-dimethyl-7H-pyrrolo[2,3-d]-pyrimidine (27mg) in toluene (1 ml) and acetonitrile (0.5 ml) under reflux,4-fluorophenyl isocyanate (13.3 μM) was added. Upon stirring for 1 hour,the mixture was returned to room temperature and the precipitatedcrystals were filtered out to obtain the title compound (26 mg).

MS (ESI) m/z 392 (M+1)

¹H-NMR (DMSO-d₆) δ (ppm): 2.31 (3H, s), 2.46-2.50 (3H, m), 6.78-7.48(8H, m), 8.14 (1H, s), 8.52 (1H, s), 8.82 (1H, s), 11.79 (1H, s)

The intermediates were synthesized in the following manner.

Production Example 128-14-(3-Nitrophenoxy)-5,6-dimethyl-7H-pyrrolo[2,3-d]-pyrimidine

After adding 3-nitrophenol (243 mg), potassium carbonate (268 mg) anddimethylformamide (2 ml) to the4-chloro-5,6-dimethyl-7H-pyrrolo[2,3-d]-pyrimidine (177 mg) described inJournal of Medicinal Chemistry, 1996, Vol. 39, No. 12, 2285-2292, themixture was stirred at 120-130° C. for 72 hours. This was returned toroom temperature, water was added, extraction was performed with atetrahydrofuran and ethyl acetate mixed solution, and then the organiclayer was washed with saturated brine, dried over anhydrous sodiumsulfate and concentrated to dryness. The obtained crystals were washedwith diethyl ether to obtain the title compound (130 mg).

MS (ESI) m/z 285 (M+1)

¹H-NMR (DMSO-d₆) δ (ppm): 2.31 (3H, s), 2.46-2.50 (3H, m), 7.70-8.18(5H, m), 11.89 (1H, s)

Production Example 128-24-(3-Aminophenoxy)-5,6-dimethyl-7H-pyrrolo[2,3-d]-pyrimidine

After adding iron powder (0.12 g), ammonium chloride (0.24 g), ethanol(5 ml) and water (1 ml) to the4-(3-nitrophenoxy)-5,6-dimethyl-7H-pyrrolo [2,3-d]-pyrimidine (110 mg)synthesized by the intermediate synthesis method described above, themixture was stirred at 80-90° C. for 3 hours. After returning thereaction system to room temperature and adding tetrahydrofuran (3 ml)and ethyl acetate (3 ml), the mixture was filtered with celite, thefiltrate was subjected to liquid separation and extraction with ethylacetate, and the organic layer was washed with water and saturated brinein that order. It was then dried over sodium sulfate, concentrated todryness under reduced pressure and washed with diethyl ether to obtainthe title compound (37 mg).

¹H-NMR (DMSO-d₆) δ (ppm): 2.27 (3H, s), 2.29 (3H, s), 5.15-5.24 (2H, m),6.28 (1H, d, J=8.1 Hz), 6.32 (1H, s), 6.40 (1H, d, J=8.1 Hz), 7.01 (1H,t, J=8.1 Hz), 8.12 (1H, s), 11.72 (1H, s).

Example 129 N-6-((6,7-Dimethoxy-4-quinolyl)oxy)-3-pyridyl-N′-phenylurea

6-((6,7-Dimethoxy-4-quinolyl)oxy)-3-pyridylamine (59.5 mg, 200 mmol) andphenyl isocyanate (26.2 mg, 220 mmol) were stirred inN,N-dimethylformamide (1 ml) at room temperature for 18 hours. Afterdiluting the reaction solution with ethyl acetate, it was washed withwater and saturated brine, the organic layer was dried over anhydrousmagnesium sulfate, the drying agent was filtered off and the filtratewas distilled off under reduced pressure. The obtained crude product wassuspended in ethyl acetate, the suspension was diluted with hexane, andthe crystals were filtered out and washed with ethyl acetate and thenblow-dried to obtain the title compound (68 mg, 163 mmol, 82%) ascolorless crystals.

¹H-NMR Spectrum: (DMSO-d₆) 3.90 (3H, s), 3.95 (3H, s), 6.55 (1H, d,J=5.2 Hz), 6.96-7.02 (1H, m), 7.26-7.32 (3H, m), 7.40 (1H, s), 7.41 (1H,s), 7.47 (2H, d, J=8.4 Hz), 8.14 (1H, dd, J=2.8, 8.8 Hz), 8.35 (1H, d,J=2.8 Hz), 8.55 (1H, d, J=5.2 Hz), 8.89 (1H, s), 8.99 (1H, s).

The intermediates were synthesized in the following manner.

Production Example 129-16,7-Dimethoxy-4-((5-nitro-2-pyridyl)oxy)quinoline

6,7-Dimethoxy-1,4-dihydro-4-quinolinone (4.10 g, 20.0 mmol),2-bromo-5-nitropyridine (4.46 g, 22.0 mmol) and potassium carbonate(5.53 g, 40.0 mmol) were heated and stirred at 70° C. for 3 hours inN,N-dimethylformamide (20 ml). The reaction solution was diluted withethyl acetate, the insoluble portion was filtered off, and after washingwith water and saturated brine and drying the organic layer overanhydrous magnesium sulfate, the drying agent was filtered off and thefiltrate was distilled off under reduced pressure. The obtained crudeproduct was subjected to silica gel column chromatography (eluent: ethylacetate), and the fraction containing the target substance wasconcentrated, suspended in ethyl acetate and diluted with hexane, afterwhich the crystals were filtered out, washed with hexane and thenblow-dried to obtain the title compound (2.23 g, 6.81 mmol, 34%) asyellow crystals.

¹H-NMR Spectrum: (CDCl₃) 3.95 (3H, s), 4.06 (3H, s), 7.07 (1H, d, J=5.2Hz), 7.16 (1H, s), 7.26 (1H, d, J=8.8 Hz), 7.49 (1H, s), 8.60 (1H, dd,J=2.8, 8.8 Hz), 8.74 (1H, d, J=5.2 Hz), 9.08 (1H, d, J=2.8 Hz).

Production Example 129-26-((6,7-Dimethoxy-4-quinolyl)oxy)-3-pyridinamine

6,7-Dimethoxy-4-((5-nitro-2-pyridyl)oxy)quinoline (654 mg, 2.00 mmol),iron powder (559 mg, 10.0 mmol) and ammonium chloride (1.07 g, 20.0mmol) were heated and stirred in ethanol (20 ml)-water (5 ml) at 80° C.for 20 minutes. After completion of the reaction, the reaction mixturewas filtered with celite and washed in ethyl acetate. After washing theorganic layer with water and saturated brine and drying over anhydrousmagnesium sulfate, the drying agent was filtered out and the filtratewas distilled off under reduced pressure. The obtained crude product wassuspended in ethyl acetate, the suspension was diluted with hexane, andthe crystals were filtered out and washed with ethyl acetate and thenblow-dried to obtain the title compound (380 mg, 1.28 mmol, 64%) aslight yellow crystals.

¹H-NMR Spectrum: (CDCl₃) 3.73 (2H, s), 4.02 (3H, s), 4.04 (3H, s), 6.61(1H, d, J=5.2 Hz), 6.96 (1H, d, J=8.8 Hz), 7.18 (1H, dd, J=2.8, 8.8 Hz),7.41 (1H, s), 7.53 (1H, s), 7.85 (1H, d, J=2.8 Hz), 8.54 (1H, d, J=5.2Hz).

Example 130N-6-((6,7-Dimethoxy-4-quinolyl)oxy)-3-pyridyl-N′-(4-fluorophenyl)urea

The title compound (67 mg, 154 mmol, 77%) was obtained as colorlesscrystals from 4-fluorophenyl isocyanate (30.1 mg, 220 mmol), by the sameprocedure as in Example 129.

¹H-NMR Spectrum: (DMSO-d₆) 3.89 (3H, s), 3.95 (3H, s), 6.79 (1H, d,J=5.0 Hz), 7.11-7.16 (2H, m), 7.29 (1H, d, J=8.6 Hz), 7.39 (1H, s), 7.41(1H, s), 7.45-7.51 (2H, m), 8.13 (1H, dd, J=2.6, 8.6 Hz), 8.34 (1H, d,J=2.6 Hz), 8.55 (1H, d, J=5.0 Hz), 8.93 (1H, s), 8.99 (1H, s).

Example 131N-6-((6,7-Dimethoxy-4-quinolyl)oxy)-3-pyridyl-N′-(1,3-thiazol-2-yl)urea

The 6-((6,7-dimethoxy-4-quinolyl)oxy)-3-pyridinamine (89.1 mg, 300 mmol)obtained in Example 129 and phenyl N-(2-thiazolyl)carbamate (79.3 mg,360 mmol) were stirred in dimethyl sulfoxide (1 ml) at 85° C. for 1hour. After diluting the reaction solution with ethyl acetate, it waswashed with water and saturated brine, the organic layer was dried overanhydrous magnesium sulfate, the drying agent was filtered off and thefiltrate was distilled off under reduced pressure. The obtained crudeproduct was suspended in ethyl acetate, the suspension was diluted withhexane, and the crystals were filtered out and washed with ethyl acetateand then blow-dried to obtain the title compound (88 mg, 208 mmol, 69%)as colorless crystals.

¹H-NMR Spectrum: (DMSO-d₆) 3.89 (3H, s), 3.95 (3H, s), 6.81 (1H, d,J=5.2 Hz), 7.12 (1H, d, J=3.6 Hz), 7.31 (1H, d, J=8.8 Hz), 7.36-7.40(2H, m), 7.42 (1H, s), 8.18 (1H, dd, J=2.8, 8.8 Hz), 8.37 (1H, d, J=2.8Hz), 8.56 (1H, d, J=5.2 Hz), 9.30 (1H, s).

Example 1324-(5-((Anilinocarbonyl)amino)-2-pyridyloxy)-7-methoxy-6-quinolinecarboxamide

The title compound (59 mg, 137 mmol, 78%) was obtained as colorlesscrystals from4-((5-amino-2-pyridyl)oxy)-7-methoxy-6-quinolinecarboxamide (55.0 mg,177 mmol), by the same procedure as in Example 129.

¹H-NMR Spectrum: (DMSO-d₆) 4.04 (3H, s), 6.86 (1H, d, J=5.2 Hz),6.96-7.02 (1H, m), 7.26-7.34 (3H, m), 7.47 (2H, d, J=7.6 Hz), 7.54 (1H,s), 7.74 (1H, s), 7.86 (1H, s), 8.15 (1H, dd, J=2.8, 8.8 Hz), 8.36 (1H,d, J=2.8 Hz), 8.55 (1H, s), 8.75 (1H, d, J=5.2 Hz), 8.90 (1H, s), 9.01(1H, s).

The intermediates were synthesized in the following manner.

Production Example 132-17-Methoxy-4-((5-nitro-2-pyridyl)oxy)-6-quinolinecarboxamide

The title compound (93.0 mg, 273 mmol, 5%) was obtained as yellowcrystals from 7-methoxy-4-oxo-1,4-hydroxy-6-quinolinecarboxamide (1.09g, 5.00 mmol) derived by hydrolysis of the7-methoxy-4-oxo-1,4-dihydro-6-quinolinecarboxamide described inWO98/13350, by the same procedure as in Example 129.

¹H-NMR Spectrum: (CDCl₃) 4.15 (3H, s), 5.92 (1H, s), 7.21 (1H, d, J=5.2Hz), 7.35 (1H, d, J=9.2 Hz), 7.63 (1H, s), 7.79 (1H, s), 8.62 (1H, dd,J=2.8, 8.8 Hz), 8.94 (1H, d, J=5.2 Hz), 8.96 (1H, s), 9.02 (1H, d, J=5.2Hz).

Production Example 132-24-((5-Amino-2-pyridyl)oxy)-7-methoxy-6-quinolinecarboxamide

7-Methoxy-4-((5-nitro-2-pyridyl)oxy)-6-quinolinecarboxamide (93.0 mg,273 mmol), iron powder (76.0 mg, 1.36 mmol) and ammonium chloride (146mg, 2.73 mmol) were heated and stirred in ethanol (4 ml)-water (1 ml) at80° C. for 20 minutes. After completion of the reaction, the reactionmixture was filtered with celite and washed in an ethylacetate-tetrahydrofuran mixed solvent. After washing the organic layerwith water and saturated brine and drying over anhydrous magnesiumsulfate, the drying agent was filtered out and the filtrate wasdistilled off under reduced pressure. The obtained crude product wassubjected to silica gel column chromatography (eluent-ethylacetate:methanol=20:1), and the fraction containing the target substancewas concentrated, suspended in ethyl acetate and diluted with hexane,after which the crystals were filtered out, washed with hexane and thenblow-dried to obtain the title compound (61.0 mg, 197 mmol, 72%) asyellow crystals.

¹H-NMR Spectrum: (DMSO-d₆) 4.03 (3H, s), 6.60 (1H, d, J=5.4 Hz), 7.04(1H, d, J=8.4 Hz), 7.18 (1H, dd, J=2.6, 8.4 Hz), 7.50 (1H, s), 7.68 (1H,d, J=2.6 Hz), 7.73 (1H, s), 7.86 (1H, s), 8.61 (1H, s), 8.67 (1H, d,J=5.4 Hz).

Example 133N-(4-(6-Cyano-7-((3-methylsulfonyl)propoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-(4-fluorophenyl)urea

The title compound (67 mg) was obtained from6-cyano-4-{4-[4-fluoroanilinocarbonyl]amino-3-fluorophenoxy}quinolin-7-olsodium salt (100 mg) in the same manner as Example 7.

¹H-NMR (DMSO-d₆) δ (ppm): 2.24-2.32 (2H, m), 3.05 (3H, s), 3.30-3.35(2H, m), 4.42 (2H, t, J=6 Hz), 6.63 (1H, d, J=5.6 Hz), 7.11-7.15 (3H,m), 7.40 (1H, dd, J=2.8 Hz, J=8.0 Hz), 7.44-7.48 (2H, m), 7.63 (1H, s),8.21-8.26 (1H, m), 8.64 (1H, br), 8.75 (1H, d, J=5.6 Hz), 8.77 (1H, s),9.10 (1H, br).

Example 134N-(4-(6-Cyano-7-((3-methylthio)propoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-(4-fluorophenyl)urea

The title compound (30 mg) was obtained from6-cyano-4-{4-[4-fluoroanilinocarbonyl]amino-3-fluorophenoxy}quinolin-7-olsodium salt (100 mg), in the same manner as Example 7.

¹H-NMR (DMSO-d₆) δ (ppm): 2.09 (3H, s), 2.06-2.14 (2H, m), 2.67 (2H, t,J=7.2 Hz), 4.37 (2H, t, J=6 Hz), 6.62 (1H, d, J=5.2 Hz), 7.10-7.15 (3H,m), 7.39 (1H, dd, J=2.8 Hz, J=7.6 Hz), 7.44-7.48 (2H, m), 7.60 (1H, s),8.21-8.26 (1H, m), 8.65 (1H, br), 8.74 (1H, d, J=5.2 Hz), 8.75 (1H, s),9.12 (1H, brd, J=3.2 Hz).

Example 135N-(4-(6-Cyano-7-(3-(ethoxycarbonyl)propoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-(4-fluorophenyl)urea

The title compound (850 mg) was obtained from6-cyano-4-{4-[4-fluoroanilinocarbonyl]amino-3-fluorophenoxy}quinolin-7-olsodium salt (1.0 g), in the same manner as Example 7.

¹H-NMR (DMSO-d₆) δ (ppm): 1.17 (3H, t, J=7.2 Hz), 2.05-2.13 (2H, m),2.53 (2H, t, J=7.2 Hz), 4.07 (2H, q, J=7.2 Hz), 4.31 (2H, t, J=6.4 Hz),6.61 (1H, d, J=5.2 Hz), 7.10-7.15 (3H, m), 7.40 (1H, dd, J=2.8 Hz, J=7.6Hz), 7.44-7.48 (2H, m), 7.60 (1H, s), 8.22-8.27 (1H, m), 8.64 (1H, br),8.74 (1H, d, J=5.2 Hz), 8.74 (1H, s), 9.10 (1H, br).

Example 136N-(4-(6-Cyano-7-(3-carboxypropoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-(4-fluorophenyl)urea

N-(4-(6-Cyano-7-(3-(ethoxycarbonyl)propoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-(4-fluorophenyl)urea(800 mg) was dissolved in methanol (45 ml), 2N NaOH water (15 ml) wasadded, and the mixture was heated and stirred for 40 minutes at 80° C.After completion of the reaction, the reaction solution was poured intoice water and neutralized with 1N HCl, and the precipitated solid wasfiltered out. The obtained solid was washed with water and dried toobtain 230 mg of the title compound.

¹H-NMR (DMSO-d₆) δ (ppm): 2.01-2.08 (2H, m), 2.46 (2H, t, J=7.6 Hz),4.30 (2H, t, J=6.4 Hz), 6.61 (1H, d, J=5.2 Hz), 7.10-7.15 (3H, m), 7.39(1H, dd, J=2.8 Hz, J=8.0 Hz), 7.44-7.48 (2H, m), 7.59 (1H, s), 8.21-8.26(1H, m), 8.66 (1H, br), 8.73 (1H, d, J=5.2 Hz), 8.74 (1H, s), 9.13 (1H,br).

Example 137N-(4-(6-Cyano-7-(3-((cyclopropylamino)carbonyl)propoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-(4-fluorophenyl)urea

N-(4-(6-Cyano-7-(3-carboxypropoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-(4-fluorophenyl)urea(100 mg) was dissolved in dimethylformamide (3 ml), and then1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (44 mg) and1-hydroxy-1H-benzotriazole (35 mg) were added while stirring on ice andthe mixture was stirred at room temperature for 30 minutes.Cyclopropylamine (16 μl) was then added and the mixture was stirred atroom temperature for 18 hours. After completion of the reaction, thereaction solution was poured into 1N sodium hydroxide water andextracted with ethyl acetate, and the obtained organic layer was washedwith saturated brine and dried over magnesium sulfate. The organic layerwas concentrated, and the obtained solid was washed with ether and asmall amount of ethyl acetate to obtain 38 mg of the title compound.

¹H-NMR (DMSO-d₆) δ (ppm): 0.34-0.38 (2H, m), 0.54-0.59 (2H, m),1.99-2.06 (2H, m), 2.25 (2H, t, J=7.2 Hz), 2.56-2.63 (1H, m), 4.27 (2H,t, J=6.4 Hz), 6.60 (1H, d, J=5.2 Hz), 7.10-7.15 (3H, m), 7.39 (1H, dd,J=2.8 Hz, J=8.0 Hz), 7.44-7.49 (2H, m), 7.59 (1H, s), 7.95 (1H, brd,J=3.6 Hz), 8.21-8.25 (1H, m), 8.67 (1H, br), 8.73 (1H, d, J=5.2 Hz),8.74 (1H, s), 9.15 (1H, br).

Example 138N-(4-(6-Cyano-7-(3-((piperidino)carbonyl)propoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-(4-fluorophenyl)urea

The title compound (33 mg) was obtained fromN-(4-(6-cyano-7-(3-carboxypropoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-(4-fluorophenyl)urea(100 mg) by the same procedure as in Example 137.

¹H-NMR (DMSO-d₆) δ (ppm): 1.38-1.60 (6H, m), 2.01-2.09 (2H, m), 2.53(2H, t, J=7.2 Hz), 3.39-3.46 (4H, m), 4.31 (2H, t, J=6.0 Hz), 6.61 (1H,d, J=5.2 Hz), 7.10-7.15 (3H, m), 7.40 (1H, dd, J=2.4 Hz, J=8.0 Hz),7.43-7.49 (2H, m), 7.61 (1H, s), 8.20-8.27 (1H, m), 8.70 (1H, br), 8.73(1H, d, J=5.2 Hz), 8.74 (1H, s), 9.17 (1H, br).

Example 139N-(4-(6-Cyano-7-(3-((dimethylamino)sulfonyl)propoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-(4-fluorophenyl)urea

The title compound (35 mg) was obtained from6-cyano-4-{4-[4-fluoroanilinocarbonyl]amino-3-fluorophenoxy}quinolin-7-olsodium salt (100 mg), in the same manner as Example 7.

¹H-NMR (DMSO-d₆) δ (ppm): 2.19-2.27 (2H, m), 2.80 (6H, s), 3.26-3.31(2H, m), 4.41 (2H, t, J=6.4 Hz), 6.63 (1H, d, J=5.2 Hz), 7.10-7.16 (3H,m), 7.40 (1H, dd, J=2.8 Hz, J=7.6 Hz), 7.44-7.49 (2H, m), 7.61 (1H, s),8.21-8.27 (1H, m), 8.68 (1H, br), 8.75 (1H, d, J=5.2 Hz), 8.77 (1H, s),9.15 (1H, br).

Example 140N-(4-(6-Cyano-7-(3-((cyclopropylamino)sulfonyl)propoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-(4-fluorophenyl)urea

The title compound (31 mg) was obtained from6-cyano-4-{4-[4-fluoroanilinocarbonyl]amino-3-fluorophenoxy}quinolin-7-olsodium salt (100 mg), in the same manner as Example 7.

¹H-NMR (DMSO-d₆) δ (ppm): 0.51-0.63 (4H, m), 2.17-2.25 (2H, m),3.15-3.22 (1H, m), 3.26-3.33 (2H, m), 4.42 (2H, t, J=6.0 Hz), 6.63 (1H,d, J=5.2 Hz), 7.10-7.16 (3H, m), 7.40 (1H, dd, J=2.8 Hz, J=8.0 Hz),7.44-7.48 (2H, m), 7.56 (1H, brd, J=2.8 Hz), 7.61 (1H, s), 8.21-8.27(1H, m), 8.63-8.66 (1H, m), 8.75 (1H, d, J=5.2 Hz), 8.77 (1H, s),9.11-9.13 (1H, m).

Example 141N-(4-(7-Benzyloxy-6-cyano-4-quinolyl)oxy-2-fluorophenyl)-N′-(2-thiazolyl)urea

Phenyl N-(4-(6-cyano-7-benzyloxy-4-quinolyl)oxy-2-fluorophenyl)carbamate(6.93 g) and 2-aminothiazole (2.75 g) were dissolved indimethylformamide (70 ml), and then diisopropylethylamine (4.8 ml) wasadded and the mixture was heated and stirred at 90° C. for 2 hours.After cooling, water was added and the precipitated solid was filteredout and washed with ethyl acetate to obtain 5.53 g of the title compoundas light brown crystals (79% yield).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 5.46 (2H, s), 6.63 (1H, d, J=5.2 Hz),7.13-7.19 (2H, m), 7.33-7.48 (5H, m), 7.54 (2H, d, J=6.8 Hz), 7.72 (1H,s), 8.21-8.27 (1H, m), 8.73-8.78 (2H, m)

The intermediates were synthesized in the following manner.

Production Example 141-1 PhenylN-(4-(6-cyano-7-benzyloxy-4-quinolyl)oxy-2-fluorophenyl)carbamate

The 7-benzyloxy-6-cyano-4-(3-fluoro-4-aminophenoxy)quinoline (9.45 g)synthesized in Production Example 8 was dissolved in dimethylformamide(70 ml) and pyridine (5.9 ml), and the mixture was cooled to 0° C. undera nitrogen atmosphere. After adding phenyl chlorocarbonate (3.4 ml), themixture was stirred for 2 hours. Water was added to the reactionsolution, and the precipitated crystals were filtered out and trituratedin tetrahydrofuran and toluene to obtain 6.93 g of the title compound aslight brown crystals (56% yield).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 5.36 (2H, s), 6.53 (1H, d, J=5.3 Hz),6.98-7.05 (2H, m), 7.17-7.47 (9H, m), 7.51-7.58 (3H, m), 8.67-8.71 (2H,m)

Example 142N-[4-(6-Cyano-7-[3-(morpholin-4-yl)propoxy]-4-quinolyl)oxy-2-fluorophenyl]-N′-(2-thiazolyl)urea

N-(4-(6-Cyano-7-hydroxyquinolyl)oxy-2-fluorophenyl)-N′-(2-thiazolyl)urea(150 mg) was dissolved in dimethylformamide (3 ml), and then potassiumcarbonate (150 mg) and 1-chloro-3-(morpholin-4-yl)propane (70 mg) wereadded and the mixture was heated and stirred at 60° C. for 2 hours.After cooling, water was added, extraction was performed with ethylacetate, the organic layer was washed with saturated brine and driedover anhydrous sodium sulfate, and the solvent was distilled off underreduced pressure. The residue was purified by NH silica gel columnchromatography (ethyl acetate-methanol system) to obtain the titlecompound (20 mg).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.94-2.04 (2H, m), 2.34-2.52 (6H, m),3.54-3.61 (4H, m), 4.34 (2H, t, J=6.2 Hz), 6.61 (1H, d, J=5.6 Hz),7.12-7.20 (2H, m), 7.37-7.47 (2H, m), 7.61 (1H, s), 8.21-8.27 (1H, m),8.73-8.76 (2H, m)

The intermediates were synthesized in the following manner.

Production Example 142-1N-(4-(6-Cyano-7-hydroxy-4-quinolyl)oxy-2-fluorophenyl)-N′-(2-thiazolyl)urea

TheN-(4-(7-benzyloxy-6-cyanoquinolyl)oxy-2-fluorophenyl)-N′-(2-thiazolyl)urea(5.53 g) synthesized in Example 141 was dissolved in TFA (55 ml), andthen thioanisole (5.5 ml) was added and the mixture was heated andstirred at 70° C. for 6 hours. After cooling the reaction solution andconcentrating it under reduced pressure, sodium bicarnobate water andmethanol were added and the precipitated crystals were filtered. Thesewere washed with diethyl ether to obtain 3.63 g of the title compound(80% yield).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 6.50 (1H, d, J=5.6 Hz), 7.12-7.19(2H, m), 7.35-7.45 (3H, m), 8.19-8.27 (1H, m), 8.61-8.66 (2H, m)

Example 143N-(4-(6-Cyano-7-(3-(diethylamino)propoxy)-4-quinolyl)oxy-2-fluorophenyl-N′-(2-thiazolyl)urea

TheN-(4-(6-cyano-7-hydroxy-4-quinolyl)oxy-2-fluorophenyl)-N′-(2-thiazolyl)urea(150 mg) synthesized in Example 142 was dissolved in dimethylformamide(2.5 ml), and then potassium carbonate (150 mg) and1-chloro-3-(diethylamino)propane (80 mg) were added and the mixture washeated and stirred at 60° C. for 2 hours. After cooling, water wasadded, extraction was performed with ethyl acetate, the organic layerwas washed with saturated brine and dried over anhydrous sodium sulfate,and the solvent was distilled off under reduced pressure. The residuewas purified by NH silica gel column chromatography (ethylacetate-methanol system) to obtain the title compound (10 mg).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.95 (6H, t, J=7.0 Hz), 1.85-1.96(2H, m), 2.40-2.65 (6H, m), 4.32 (2H, t, J=6.0 Hz), 6.62 (1H, d, J=5.2Hz), 7.12-7.20 (2H, m), 7.36-7.48 (2H, m), 7.59 (1H, s), 8.20-8.24 (1H,m), 8.73-8.77 (2H, m)

Example 144N-(4-(6-Cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)-N′-(3-methylisoxazol-5-yl)urea

The 4-(4-aminophenoxy)-6-cyano-7-(2-methoxyethoxy)quinoline (100 mg)synthesized in Production Example 10 and phenylN-(3-methylisoxazol-5-yl)carbamate (81 mg) were added to toluene (5 ml),then diisopropylethylamine (0.88 ml) was added and the mixture washeated and stirred at 100° C. for 2 hours. After cooling, theprecipitated crystals were filtered and washed with an ethylacetate:toluene (1:1) mixed solvent to obtain the title compound (102mg).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.16 (3H, s), 3.36 (3H, s), 3.76-3.79(2H, m), 4.40-4.44 (2H, m), 5.95 (1H, s), 6.52 (1H, d, J=5.2 Hz), 7.26(2H, d, J=9.2 Hz), 7.58-7.64 (3H, m), 8.71 (1H, d, J=5.2 Hz), 8.76 (1H,s), 9.04 (1H, brs).

The intermediates were synthesized in the following manner.

Production Example 144-1 Phenyl N-(3-Methylisoxazol-5-yl)carbamate

5-Amino-3-methylisoxazole (1 g) purchased from Aldrich Co. was dissolvedin tetrahydrofuran (40 ml) and pyridine (1.5 ml), and after cooling to0° C. under a nitrogen atmosphere, phenyl chlorocarbonate (1.4 ml) wasadded and the mixture was stirred at room temperature for 1.5 hours.Water was added, extraction was performed twice with ethyl acetate, andthen the organic layers were combined, washed with water and saturatedbrine in that order, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The obtained residue wasrecrystallized from ethyl acetate and n-hexane to obtain the titlecompound (450 mg, 20% yield).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 2.27 (3H, s), 6.03 (1H, s), 7.16-7.30(3H, m), 7.37-7.44 (2H, m), 7.81 (1H, brs)

Example 145N-(4-(6-Cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)-N′-(5-methylisoxazol-3-yl)urea

The 4-(4-aminophenoxy)-6-cyano-7-(2-methoxyethoxy)quinoline (100 mg)synthesized in Production Example 10 and phenylN-(5-methylisoxazol-3-yl)carbamate (72 mg) were added to toluene (5 ml),and then diisopropylethylamine (0.50 ml) was added and the mixture washeated to reflux for 2 hours. After cooling, the precipitated crystalswere filtered and washed with an ethyl acetate/toluene (1/1) mixedsolvent to obtain the title compound (120 mg).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.36 (3H, s), 3.37 (3H, s) 3.75-3.78(2H, m), 4.37-4.43 (2H, m), 6.50-6.54 (2H, m), 7.26 (2H, d, J=8.8 Hz),7.56-7.63 (3H, m), 8.72 (1H, d, J=5.6 Hz), 8.76 (1H, s), 8.99 (1H, brs),9.51 (1H, brs)

The intermediates were synthesized in the following manner.

Production Example 145-1 Phenyl N-(5-Methylisoxazol-3-yl)carbamate

3-Amino-5-methylisoxazole (1.00 g) purchased from Aldrich Co. wasdissolved in tetrahydrofuran (20 ml) and pyridine (1.5 ml), and aftercooling to 0° C. under a nitrogen atmosphere, phenyl chlorocarbonate(1.4 ml) was added and the mixture was stirred at room temperature for 2hours. Water was added, extraction was performed twice with ethylacetate, and then the organic layers were combined, washed with waterand saturated brine in that order, dried over anhydrous sodium sulfateand concentrated under reduced pressure. The obtained residue wastriturated with diethyl ether and n-hexane to obtain the title compound(1.54 g) (68% yield).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 2.42 (3H, s), 6.56 (1H, s), 7.15-7.30(3H, m), 7.36-7.43 (2H, m), 8.18 (1H, brs)

Example 146N-(4-(6-Cyano-7-(2-methoxyethoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-(2-oxo-1,2,3,4-tetrahydro-6-quinolinyl)urea

The title compound (64 mg) was obtained from phenylN-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxy-2-fluorophenyl)carbamate(65 mg), in the same manner as Example 25.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.38-2.45 (2H, m), 2.81-2.90 (2H, m),3.36 (3H, s), 3.75-3.79 (2H, m), 4.40-4.43 (2H, m), 6.61 (1H, d, J=5.2),6.77 (1H, d, J=8.4 Hz), 7.10-7.18 (2H, m), 7.30 (1H, brs), 7.36-7.42(1H, m), 7.63 (1H, s), 8.23-8.29 (1H, m), 8.60 (1H, brs), 8.73-8.76 (2H,m), 8.92-8.94 (1H, m), 9.97 (1H, brs)

Example 1474-(4-(Anilinocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide

The N-(4-(6-cyano-7-methoxy-4-quinolyl)oxyphenyl)-N′-phenylurea (100 mg)synthesized in Example 37 was dissolved in dimethylsulfoxide (3 ml) at80° C., and then 5N aqueous sodium hydroxide was added and the mixturewas heated and stirred for 2 hours. The reaction solution wasneutralized with 1N hydrochloric acid, and the precipitated crystalswere filtered out and washed with ethanol to obtain the title compound(60 mg).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 4.03 (3H, s), 6.56 (1H, d, J=6.0 Hz),6.96 (1H, t, J=7.6 Hz), 7.22-7.30 (4H, m), 7.45 (2H, d, J=7.6 Hz), 7.52(1H, s), 7.59-7.62 (2H, m), 7.76 (1H, brs), 7.87 (1H, brs), 8.69-8.73(2H, m), 8.76 (1H, brs), 8.90 (1H, brs)

Example 1484-(4-(Anilinocarbonyl)aminophenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxamide

The title compound (54 mg) was obtained from theN-(4-(6-cyano-7-(methoxyethoxy)-4-quinolyl)oxyphenyl)-N′-phenylurea (95mg) synthesized in Example 65, in the same manner as Example 147.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.35 (3H, s), 3.75-3.81 (2H, m),4.37-4.41 (2H, m), 6.46 (1H, d, J=5.2), 6.96 (1H, t, J=7.6), 7.21-7.30(4H, m), 7.45 (2H, d, J=8.4 Hz), 7.55 (1H, s), 7.59 (2H, d, J=8.8 Hz),7.81 (1H, brs), 7.82 (1H, brs), 8.65 (1H, d, J=5.2), 8.77-8.79 (2H, m),8.91 (1H, brs)

Example 1494-(4-((2,4-Difluorophenyl)carbonyl)amino-3-fluorophenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxamide

The title compound (35 mg) was obtained from theN-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-(2,4-difluorophenyl)urea(100 mg) synthesized in Example 66, in the same manner as Example 147.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.34 (3H, s), 3.78-3.81 (2H, m),4.39-4.42 (2H, m), 6.56 (1H, d, J=5.2 Hz), 7.03-7.17 (2H, m), 7.28-7.43(2H, m), 7.56 (1H, s), 7.81 (2H, brs), 8.08-8.16 (1H, m), 8.28-8.29 (1H,m), 8.67 (1H, d, J=5.2), 8.76 (1H, s), 9.00-9.09 (2H, m)

Example 1504-(4-((4-Fluoroanilino)carbonyl)amino-3-fluorophenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxamide

The title compound (25 mg) was obtained from theN-(4-(6-cyano-7-(2-ethoxyethoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-(4-fluorophenyl)urea(58 mg) synthesized in Example 100, in the same manner as Example 147.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.34 (3H, s), 3.78-3.81 (2H, m),4.39-4.42 (2H, m), 6.56 (1H, d, J=5.2 Hz), 7.10-7.17 (3H, m), 7.36-7.50(3H, m), 7.56 (1H, s), 7.82 (2H, brs), 8.19-8.26 (1H, m), 8.64-8.69 (2H,m), 8.76 (1H, s), 9.13-9.15 (1H, m)

Example 1517-(2-Methoxyethoxy)-4-(4-((1,3-thiazol-2-ylamino)carbonyl)amino-3-fluorophenoxy)-6-quinolinecarboxamide

The title compound (18 mg) was obtained from theN-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-(1,3-thiazol-2-yl)urea(100 mg) synthesized in Example 25, in the same manner as Example 147.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.34 (3H, s), 3.78-3.81 (2H, m),4.39-4.42 (2H, m), 6.57 (1H, d, J=5.2 Hz), 7.12-7.19 (2H, m), 7.39 (1H,d, J=3.6 Hz), 7.41-7.46 (1H, m), 7.57 (1H, s), 7.82 (1H, brs), 8.21-8.25(1H, m), 8.68 (1H, d, J=5.2 Hz), 8.76 (1H, s), 9.06 (1H, brs)

Example 1524-(4-((4-Fluoroanilino)carbonyl)amino-3-fluorophenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (25 mg) was obtained from6-carbamoyl-4-(4-amino-3-fluorophenoxy)-7-methoxyquinoline (50 mg), inthe same manner as Example 10.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 4.02 (3H, s), 6.55 (1H, d, J=5.6 Hz),7.09-7.18 (3H, m), 7.35-7.41 (1H, m), 7.43-7.49 (2H, m), 7.51 (1H, s),7.74 (1H, brs), 7.85 (1H, brs), 8.18-8.26 (1H, m), 8.61-8.68 (3H, m),9.09-9.12 (1H, m)

The starting compounds were synthesized in the following manner.

Production Example 152-17-Methoxy-4-oxo-1,4-dihydroquinoline-6-carboxylic acid

Glycerol (20 ml) and potassium hydroxide (KOH, 3.0 g) were added to the7-methoxy-4-oxo-1,4-dihydroquinoline-6-carbonitrile (2 g) of ProductionExample 24, and after heating and stirring at 160° C. for 3 hours, water(40 ml) was added and the mixture was heated at 80° C. for 30 minutes.After cooling, 2N hydrochloric acid was added to acidity and theprecipitated insoluble portion was filtered out, washed with water andthen dried under reduced pressure to obtain the title compound (1.6 g).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 4.87 (3H, s), 6.14 (1H, d, J=6.0 Hz),7.04 (1H, s), 7.98 (1H, d, J=6.0), 8.40 (1H, s)

Production Example 152-2 7-Methoxy-4-chloroquinoline-6-carbonyl chloride

Thionyl chloride (10 ml) and a small amount of dimethylformamide (DMF)were added to 7-methoxy-4-oxo-1,4-dihydroquinoline-6-carboxylic acid(2.0 g), and the mixture was heated to reflux for 2 hours. Afterconcentrating under reduced pressure, azeotropic distillation wasperformed twice with toluene to obtain the title compound (2.7 g).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 4.20 (3H, s), 7.80-7.90 (1H, m), 8.41(1H, s), 8.90-9.00 (2H, m)

Production Example 152-3 7-Methoxy-4-chloroquinoline-6-carboxamide

7-Methoxy-4-chloroquinoline-6-carbonyl chloride (2.7 g) was dissolved intetrahydrofuran (150 ml), and the solution was cooled to 0° C. Afteradding 30% ammonia water (5 ml), the mixture was stirred at roomtemperature for 30 minutes. Water was added, extraction was performed 3times with ethyl acetate, and then the organic layers were combined,washed with water and saturated brine, dried over sodium sulfate anddried under reduced pressure to obtain the title compound (1.35 g).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 4.03 (3H, s), 7.56-7.66 (2H, m), 7.79(1H, brs), 7.88 (1H, brs), 8.46-8.49 (1H, m), 8.78-8.82 (1H, m)

Production Example 152-46-Carbamoyl-4-(3-fluoro-4-nitrophenoxy)-7-methoxyquinoline

The title compound (1.1 g) was obtained from7-methoxy-4-chloroquinoline-6-carboxamide (1.23 g), in the same manneras Example 7.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 4.03 (3H, s), 6.96 (1H, d, J=5.2 Hz),7.25-7.30 (1H, m), 7.57 (1H, s), 7.61-7.66 (1H, m), 7.74 (1H, brs), 7.84(1H, brs), 8.25-8.32 (1H, m), 8.49 (1H, s), 8.80 (1H, d, J=5.2 Hz)

Production Example 152-56-Carbamoyl-4-(4-amino-3-fluorophenoxy)-7-methoxyquinoline

The title compound (540 mg) was obtained from6-carbamoyl-4-(3-fluoro-4-nitrophenoxy)-7-methoxyquinoline (1.08 g), inthe same manner as Production Example 10.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 4.01 (3H, s), 5.19-5.23 (2H, m), 6.44(1H, d, J=5.2), 6.83-6.89 (2H, m), 7.05-7.10 (1H, m), 7.47 (1H, s), 7.71(1H, brs), 7.83 (1H, brs), 8.60-8.66 (2H, m)

Example 1531-(2-Chloro-4-{6-[4-(2-diethylaminoethoxy)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy}phenyl)-3-cyclopropylurea

1-{2-Chloro-4-[6-[4-(2-diethylaminoethoxy)-phenyl]-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]-phenyl}-3-cyclopropylurea(40 mg, 0.0601 mmol) was dissolved in 1 ml of tetrahydrofuran, and then0.5 ml (8.3 equivalents) of tetrabutylammonium fluoride (1Mtetrahydrofuran solution) was added dropwise and the mixture wasrefluxed for 2 hours. After returning to room temperature, 3 ml of waterwas added, the mixture was allowed to stand for 3 hours, and theprecipitating crystals were filtered out, washed with water andether:hexane=1:1 and dried under reduced pressure to obtain 22 mg of thetitle compound.

MS Spectrum (ESI): 535 (M+1),

¹H-NMR Spectrum: (DMSO-d₆) 0.40-0.54 (2H, m), 0.70-0.80 (2H, m), 1.06(6H, t, J=7.8 Hz) 2.55-2.70 (5H, m), 2.88 (2H, t, J=7.8 Hz), 4.18 (2H,t, J=7.8 Hz), 7.01 (1H, d, J=1.7 Hz), 7.12 (2H, d, J=8.4 Hz), 7.23 (1H,d, J=2.5 Hz), 7.27 (1H, dd, J=8.8 Hz, J′=2.5 Hz), 7.41 (1H, d, J=2.5Hz), 7.97 (2H, d, J=8.4 Hz), 8.01 (1H, s), 8.24 (1H, d, J=8.8 Hz), 8.36(1H, s), 12.68 (1H, brs)

The intermediates were synthesized in the following manner.

Production Example 153-12-Amino-5-(4-benzyloxyphenyl)-1H-pyrrole-3-carboxylic acid ethyl ester

After adding 700 ml of ethanol to 50.7 g of ethyl 2-amidinoacetatehydrochloride (a publicly known compound described in Liebigs Ann.Chem., 1895(1977)), the mixture was stirred at room temperature, 22.3 gof sodium ethoxide (1 equivalent with respect to ethyl 2-amidinoacetatehydrochloride) was added, and the mixture was stirred for 15 minutesunder a nitrogen atmosphere. To this there was added 49.9 g of1-(4-benzyloxyphenyl)-2-bromoethanone (publicly known compound describedin Journal of Heterocyclic Chemistry, vol. 2, 310(1965) and Journal ofMedicinal Chemistry, vol. 17, 55(1974)), and the mixture was stirred for36 hours at room temperature under a nitrogen atmosphere. Water wasadded, ethyl acetate was used for liquid separation and extraction, andthen the organic layer was dried over sodium sulfate and concentrated todryness to obtain 56.7 g of the title compound.

¹H-NMR Spectrum: (DMSO-d₆) 1.32 (3H, t, J=7.3 Hz), 4.10 (2H, q, J=7.3Hz), 5.08 (2H, s,), 5.62 (2H, s), 6.30 (1H, d, J=2.2 Hz), 6.95 (2H, d,J=7.9 Hz), 7.28-7.47 (7H, m), 10.67 (1H, brs)

Production Example 153-26-(4-Benzyloxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ol

After adding 84 ml of formic acid, 338 ml of formamide and 169 ml ofdimethylformamide to 56.7 g of the ethyl2-amino-5-(4-benzyloxyphenyl)-1H-pyrrole-3-carboxylate synthesized inProduction Example 153-1, the mixture was stirred at 140° C. for 48hours and then allowed to stand at room temperature for 24 hours. Theprecipitated solid was filtered out and dried under reduced pressure toobtain 41 g of the title compound.

¹H-NMR Spectrum: (DMSO-d₆) 5.12 (2H, s), 6.78 (1H, s), 7.03 (2H, d,J=7.0 Hz), 7.28-7.47 (5H, m), 7.73 (2H, d, J=7.0 Hz), 7.82 (1H, s),11.80 (1H, brs), 12.20 (1H, brs)

Production Example 153-36-(4-Benzyloxyphenyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidine

After adding 200 ml of phosphorus oxychloride to 20 g of the6-(4-benzyloxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ol synthesized inProduction Example 153-2, the mixture was stirred at 140° C. for 3 hoursand the reaction mixture was cooled to room temperature and the reactionmixture was concentrated. Ice water was added to the residue, and liquidseparation and extraction were performed with an ethylacetate:tetrahydrofuran (5:1) mixed solvent. The organic layer waswashed with water and saturated brine, dried over sodium sulfate andconcentrated to dryness to obtain 12 g of the title compound.

¹H-NMR Spectrum: (DMSO-d₆) 5.18 (2H, s), 6.97 (1H, d, J=2.4 Hz), 7.12(2H, d, J=7.5 Hz), 7.30-7.50 (5H, m), 7.94 (2H, d, J=7.5 Hz), 8.70 (1H,s), 12.90 (1H, brs)

Production Example 153-46-(4-Benzyloxyphenyl)-4-chloro-7-(2-trimethylsilanylethoxy-methyl)-7H-pyrrolo[2,3-d]pyrimidine

After adding 0.381 g (1.3 equivalents) of sodium hydride (60%dispersion, Aldrich) to a solution of 2.46 g of the6-(4-benzyloxyphenyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidine synthesizedin Production Example 153-3 in dimethylformamide (30 ml), the mixturewas stirred at room temperature for 40 minutes, 1.68 ml (1.3equivalents) of 2-(chloromethoxy)ethyltrimethylsilane was added, themixture was stirred at room temperature overnight, and then 20 ml ofwater and 1 ml of acetic acid were added and liquid separation andextraction were performed with an ethyl acetate:tetrahydrofuran (5:1)mixed solvent. The organic layer was dried over sodium sulfate,concentrated and subjected to NH silica gel column chromatography (ethylacetate) to obtain 2.83 g of the title compound.

¹H-NMR Spectrum: (DMSO-d₆) −0.10 (9H, s), 0.84 (2H, t, J=8.0 Hz), 3.62(2H, t, J=8.0 Hz), 5.20 (2H, s), 5.61 (2H, s), 6.81 (1H, s), 7.19 (2H,d, J=7.7 Hz), 7.33-7.52 (5H, m), 7.88 (2H, d, J=7.7 Hz), 8.70 (1H, s)

Production Example 153-54-[6-(4-Benzyloxyphenyl)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]-2-chlorophenylamine

After adding 12 ml of dimethylsulfoxide to the6-(4-benzyloxyphenyl)-4-chloro-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidinesynthesized in Production Example 153-4, 141 mg (1.5 equivalents) ofsodium hydride (60% dispersion, Aldrich) and 507 mg (1.5 equivalents) of4-amino-3-chlorophenol were added while stirring, and stirring was thencontinued at room temperature for 10 minutes and then at 135-140° C. for4 hours. The mixture was returned to room temperature, water was added,and liquid separation and extraction were performed with an ethylacetate:tetrahydrofuran (5:1) mixed solvent. The organic layer was driedover sodium sulfate, concentrated and subjected to NH silica gel columnchromatography (hexane-ethyl acetate) to obtain 1.20 g of the titlecompound.

¹H-NMR Spectrum: (DMSO-d₆) −0.90 (9H, s), 0.85 (2H, t, J=8.0 Hz), 3.61(2H, t, J=8.0 Hz), 5.18 (2H, s), 5.34 (2H, s), 5.59 (2H, s), 6.64 (1H,s,), 6.85 (1H, d, J=8.0 Hz), 6.95-6.99 (1H, m), 7.15-7.20 (3H, m),7.30-7.55 (5H, m), 7.71 (2H, d, J=8.0 Hz), 8.41 (1H, d, J=1.4 Hz)

Production Example 153-61-{4-[6-(4-Benzyloxyphenyl)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]-2-chlorophenyl}-3-cyclopropylurea

After dissolving 334 mg of the4-[6-(4-benzyloxyphenyl)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]-2-chlorophenylaminesynthesized in Production Example 153-5 in 4 ml of dimethylformamide,0.066 ml (1.4 equivalents) of pyridine and 0.102 ml (1.4 equivalents) ofphenyl chlorocarbonate were added, and after stirring at roomtemperature for 2.5 hours, 0.09 ml (2.2 equivalents) of cyclopropylaminewas added and the mixture was stirred overnight. Water was added, liquidseparation and extraction were performed with ethyl acetate, and theorganic layer was washed with saturated brine, dried over sodiumsulfate, concentrated and subjected to silica gel column chromatography(hexane-ethyl acetate) to obtain 330 mg of the title compound.

MS Spectrum (ESI): 656 (M+1), 678 (M+23),

¹H-NMR Spectrum: (DMSO-d₆) −0.09 (9H, s), 0.40-0.46 (2H, m), 0.63-0.70(2H, m), 0.87 (2H, t, J=7.8 Hz), 2.43-2.62 (1H, m), 3.62 (2H, t, J=7.8Hz), 5.20 (2H, s), 5.60 (2H, s), 6.75 (1H, s), 7.15-7.53 (9H, m), 7.73(2H, d, J=8.6 Hz), 7.94 (1H, s), 7.93 (1H, s), 8.18 (1H, d, J=9.0 Hz),8.41 (1H, d, J=1.8 Hz)

Production Example 153-71-{2-Chloro-4-[6-(4-hydroxyphenyl)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]-2-phenyl}-3-cyclopropylurea

After dissolving 260 mg of the1-{4-[6-(4-benzyloxyphenyl)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]-2-chlorophenyl}-3-cyclopropylureasynthesized in Production Example 153-6 in 10 ml of ethanol and 5 ml oftetrahydrofuran, 100 mg of platinum oxide was added and the mixture wasstirred overnight at room temperature and normal pressure under ahydrogen atmosphere. It was then filtered with celite and concentratedunder reduced pressure. The residue was subjected to silica gel columnchromatography (hexane-ethyl acetate) to obtain 160 mg of the titlecompound.

¹H-NMR Spectrum: (DMSO-d₆) −0.09 (9H, s), 0.40-0.46 (2H, m), 0.63-0.70(2H, m), 0.86 (2H, t, J=8.1 Hz), 2.53-2.62 (1H, m), 3.62 (2H, t, J=8.1Hz), 5.58 (2H, s), 6.67 (1H, s,), 6.90 (2H, d, J=8.2 Hz), 7.13-7.22 (2H,m), 7.43-7.47 (1H, m), 7.60 (2H, d, J=8.2 Hz), 7.93 (1H, s), 8.17 (1H,d, J=9.1 Hz), 8.40 (1H, s), 9.38 (1H, brs)

Production Example 153-81-{2-Chloro-4-[6-[4-(2-diethylamino-2-hydroxypropoxy)-phenyl]-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]-phenyl}-3-cyclopropylurea

After dissolving 113 mg of the1-{2-chloro-4-[6-(4-hydroxyphenyl)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]-2-phenyl}-3-cyclopropylureasynthesized in Production Example 153-7 in 1 ml of dimethylformamide,120 mg (3.5 equivalents) of 2-chloroethyldiethylamine hydrochloride and138 mg (5 equivalents) of potassium carbonate were added and the mixturewas stirred at 80° C. for 15 hours. The mixture was then returned toroom temperature, water was added, and liquid separation and extractionwere performed with ethyl acetate. The organic layer was dried oversodium sulfate, concentrated and subjected to NH silica gel columnchromatography (hexane-ethyl acetate) to obtain 40 mg of the titlecompound.

MS Spectrum (ESI): 665 (M+1),

¹H-NMR Spectrum: (DMSO-d₆) −0.09 (9H, s), 0.40-0.47 (2H, m), 0.63-0.70(2H, m), 0.87 (2H, t, J=8.9 Hz), 0.99 (6H, t, J=8.0 Hz) 2.52-2.62 (5H,m), 2.80 (2H, t, J=8.0 Hz), 3.62 (2H, t, J=8.9 Hz), 4.10 (2H, t, J=8.0Hz), 5.60 (2H, s), 6.72 (1H, s), 7.08 (2H, d, J=8.1 Hz), 7.17 (1H, d,J=3.2 Hz), 7.21 (1H, dd, J=3.2, 8.4 Hz), 7.46 (1H, d, J=3.2 Hz), 7.71(2H, d, J=8.1 Hz), 7.94 (1H, s), 8.18 (1H, d, J=8.4 Hz), 8.40 (1H, s,)

Example 1541-(2-Chloro-4-{6-[4-(2-(1-pyrrolidino)ethoxy)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy}phenyl)-3-cyclopropylurea

The title compound (13 mg) was obtained from 25 mg of1-{2-chloro-4-[6-[4-(2-pyrrolidinoethoxy)-phenyl]-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]-phenyl}-3-cyclopropylurea,in the same manner as Example 153.

MS Spectrum (ESI): 533 (M+1),

¹H-NMR Spectrum: (DMSO-d₆) 0.40-0.45 (2H, m), 0.60-0.70 (2H, m),1.65-1.72 (4H, m), 2.47-2.60 (5H, m, covered by DMSO peak), 2.70 (2H, t,J=7.6 Hz), 4.12 (2H, t, J=7.6 Hz), 6.82 (1H, s), 7.02 (2H, d, J=8.5 Hz),7.13 (1H, d, J=2.6 Hz), 7.17 (1H, dd, J=2.6, 8.5 Hz), 7.41 (1H, d, J=2.6Hz), 7.87 (2H, d, J=8.5 Hz), 7.91 (1H, s), 8.14 (1H, d, J=8.5 Hz), 8.26(1H, s), 12.59 (1H, brs)

Production Example 154-11-{2-Chloro-4-[6-[4-(2-(1-pyrrolidino)ethoxy)-phenyl]-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]phenyl}-3-cyclopropylurea

The title compound (27 mg) was obtained from 86 mg of the1-{2-chloro-4-[6-(4-hydroxyphenyl)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]-2-phenyl}-3-cyclopropylureasynthesized in Production Example 153-7, using 104 mg of1-(2-chloroethyl)pyrrolidine hydrochloride and 126 mg of potassiumcarbonate, in the same manner as Production Example 153-8.

MS Spectrum (ESI): 663 (M+1),

¹H-NMR Spectrum: (DMSO-d₆) −0.09 (9H, s), 0.40-0.44 (2H, m), 0.61-0.69(2H, m), 0.85 (2H, t, J=8.0 Hz), 1.61-1.76 (4H, m), 2.44-2.61 (5H, m,covered by DMSO peak), 2.86 (2H, t, J=8.0 Hz), 3.61 (2H, t, J=8.0 Hz),4.13 (2H, t, J=8.0 Hz), 5.79 (2H, s), 6.72 (1H, s), 7.09 (2H, d, J=8.7Hz), 7.15 (1H, d, J=8.7 Hz), 7.20 (1H, dd, J=2.5, 8.7 Hz), 7.44 (1H, d,J=2.5 Hz), 7.71 (2H, d, J=8.7 Hz), 7.93 (1H, s), 8.16 (1H, d, J=8.7 Hz),8.39 (1H, s)

Example 1551-(2-Chloro-4-{6-[4-(2-(1-pyrrolidino)propoxy)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy}phenyl)-3-cyclopropylurea

The title compound (11 mg) was obtained from 28 mg of1-{2-chloro-4-[6-[4-(2-(1-pyrrolidino)propoxy)phenyl]-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]phenyl}-3-cyclopropylurea,in the same manner as Example 153.

MS Spectrum (ESI): 547 (M+1),

Production Example 155-11-{2-Chloro-4-[6-[4-(3-(1-pyrrolidino)propoxy)phenyl]-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]phenyl}-3-cyclopropylurea

The title compound (28 mg) was obtained from 96 mg of the1-{2-chloro-4-[6-(4-hydroxyphenyl)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]-2-phenyl}-3-cyclopropylureasynthesized in Production Example 153-7, using 146 mg of1-(3-chloropropyl)pyrrolidine, 150 mg of potassium carbonate and 15 mgof potassium iodide, in the same manner as Production Example 153-8.

MS Spectrum (ESI): 677 (M+1),

¹H-NMR Spectrum: (DMSO-d₆) −0.09 (9H, s), 0.39-0.47 (2H, m), 0.63-0.70(2H, m), 0.87 (2H, t, J=8.0 Hz), 1.63-1.73 (4H, m), 1.88-1.96 (2H, m),2.40-2.62 (7H, m, covered by DMSO peak), 3.61 (2H, t, J=8.1 Hz), 4.09(2H, t, J=6.6 Hz), 5.60 (2H, s), 6.72 (1H, s), 7.08 (2H, d, J=8.9 Hz),7.16 (1H, d, J=2.6 Hz), 7.21 (1H, dd, J=2.4, 8.9 Hz), 7.46 (1H, d, J=2.6Hz), 7.71 (2H, d, J=8.9 Hz), 7.95 (1H, s), 8.18 (1H, d, J=8.9 Hz), 8.40(1H, s)

Example 1561-{2-Chloro-4-[6-[4-((2R)-2-hydroxy-3-diethylaminopropoxy)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]phenyl}-3-cyclopropylurea

The title compound (11 mg) was obtained from 22 mg of1-{2-chloro-4-[6-[4-((2S)-2-hydroxy-3-diethylaminopropoxy)phenyl]-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]phenyl}-3-cyclopropylurea,in the same manner as Example 153.

MS Spectrum (ESI): 565 (M+1),

¹H-NMR Spectrum: (DMSO-d₆) 0.40-0.47 (2H, m), 0.63-0.70 (2H, m), 0.96(6H, t, J=6.6 Hz) 2.45-2.63 (7H, m, covered by DMSO peak), 3.80-4.10(3H, m), 6.93 (1H, s), 7.04 (2H, d, J=8.6 Hz), 7.15 (1H, d, J=2.2 Hz),7.19 (1H, dd, J=2.2, 8.6 Hz), 7.43 (1H, d, J=2.2 Hz), 7.88 (2H, d, J=8.6Hz), 7.93 (1H, s), 8.16 (1H, d, J=8.6 Hz), 8.28 (1H, s), 12.60 (1H, brs)

Production Example 156-11-{2-Chloro-4-[6-[4-((2S)-2-hydroxy-3-diethylaminopropoxy)phenyl]-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]phenyl}-3-cyclopropylurea

After dissolving 75 mg of the1-{2-chloro-4-[6-(4-hydroxyphenyl)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]-2-phenyl}-3-cyclopropylureasynthesized in Production Example 153-7 in 1 ml of dimethylformamide, 91mg (3 equivalents) of (2S)-(+)-glycidyl p-toluenesulfonate and 92 mg (5equivalents) of potassium carbonate were added, and the mixture wasstirred at 75° C. for 8 hours. After returning it to room temperature,the reaction system was filtered with a Kiriyama funnel, 0.1 ml ofdiethylamine was added to the filtrate, and the mixture was stirred at70° C. for 8 hours. Water was then added, and liquid separation andextraction were performed with ethyl acetate and tetrahydrofuran. Theorganic layer was concentrated and subjected to NH silica gel columnchromatography (hexane-ethyl acetate) to obtain 24 mg of the titlecompound.

MS Spectrum (ESI): 695 (M+1),

¹H-NMR Spectrum: (DMSO-d₆) −0.09 (9H, s), 0.39-0.47 (2H, m), 0.63-0.70(2H, m), 0.86 (2H, t, J=8.3 Hz), 0.97 (6H, t, J=7.0 Hz,), 2.38-2.60 (7H,m), 3.61 (2H, t, J=8.3 Hz), 3.83-4.11 (3H, m), 4.82 (1H, brs), 5.59 (2H,s), 6.73 (1H, s), 7.08 (2H, d, J=8.5 Hz), 7.18 (1H, d, J=2.7 Hz), 7.21(1H, dd, J=2.7, 8.5 Hz), 7.45 (1H, d, J=2.7 Hz), 7.71 (2H, d, J=8.5 Hz),7.94 (1H, s), 8.18 (1H, d, J=8.5 Hz), 8.40 (1H, s,)

Example 1571-{2-Chloro-4-[6-[4-((2R)-2-hydroxy-3-diethylaminopropoxy)phenyl]-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]phenyl}-3-cyclopropylurea

The title compound (11 mg) was obtained from 22 mg of1-{2-chloro-4-[6-[4-((2R)-2-hydroxy-3-diethylaminopropoxy)phenyl]-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]phenyl}-3-cyclopropylurea,in the same manner as Example 153.

MS Spectrum (ESI): 565 (M+1),

¹H-NMR Spectrum: (DMSO-d₆) 0.40-0.47 (2H, m), 0.63-0.70 (2H, m), 0.96(6H, t, J=6.6 Hz) 2.45-2.63 (7H, m, covered by DMSO peak), 3.80-4.10(3H, m), 6.93 (1H, s), 7.04 (2H, d, J=8.6 Hz), 7.16 (1H, d, J=2.2 Hz),7.19 (1H, dd, J=2.2, 8.6 Hz), 7.43 (1H, d, J=2.2 Hz), 7.89 (2H, d, J=8.6Hz), 7.94 (1H, s), 8.16 (1H, d, J=8.6 Hz), 8.28 (1H, s) 12.60 (1H, brs)

Production Example 157-11-{2-Chloro-4-[6-[4-((2R)-2-hydroxy-3-diethylaminopropoxy)phenyl]-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]phenyl}-3-cyclopropylurea

The title compound (62 mg) was obtained from 127 mg of1-{2-chloro-4-[6-(4-hydroxyphenyl)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]-2-phenyl}-3-cyclopropylurea,using 154 mg of (2R)-(−)-glycidyl p-toluenesulfonate, 155 mg ofpotassium carbonate and 0.15 ml of diethylamine, in the same manner asProduction Example 153-9.

MS Spectrum (ESI): 695 (M+1),

¹H-NMR Spectrum: (DMSO-d₆) −0.09 (9H, s), 0.39-0.47 (2H, m), 0.63-0.70(2H, m), 0.86 (2H, t, J=8.3 Hz), 0.97 (6H, t, J=7.0 Hz) 2.38-2.60 (7H,m, covered by DMSO peak), 3.61 (2H, t, J=8.3 Hz), 3.83-4.11 (3H, m),4.82 (1H, brs), 5.60 (2H, s), 6.73 (1H, s), 7.09 (2H, d, J=8.5 Hz), 7.16(1H, d, J=2.7 Hz), 7.20 (1H, dd, J=2.7, 8.5 Hz), 7.45 (1H, d, J=2.7 Hz),7.71 (2H, d, J=8.5 Hz), 7.94 (1H, s), 8.18 (1H, d, J=8.5 Hz), 8.40 (1H,s)

Example 1581-(2-Chloro-4-{6-[4-((2S)-2-hydroxy-3-pyrrolidinopropoxy)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]phenyl}-3-cyclopropylurea

The title compound (14 mg) was obtained from 30 mg of1-{2-chloro-4-[6-[4-(2-hydroxy-3-pyrrolidinopropoxy)phenyl]-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]phenyl}-3-cyclopropylurea,in the same manner as Example 153.

MS Spectrum (ESI): 563 (M+1),

¹H-NMR Spectrum: (DMSO-d₆) 0.40-0.47 (2H, m), 0.60-0.70 (2H, m),1.62-1.74 (4H, m), 2.40-2.70 (7H, m, covered by DMSO peak), 3.88-4.10(3H, m), 4.92 (1H, brs) 6.94 (1H, s), 7.04 (2H, d, J=8.6 Hz), 7.15 (1H,d, J=2.4 Hz), 7.20 (1H, dd, J=2.4, 8.6 Hz), 7.44 (1H, d, J=2.4 Hz), 7.88(2H, d, J=8.6 Hz), 7.94 (1H, s,), 8.16 (1H, d, J=8.6 Hz), 8.28 (1H, s)12.60 (1H, brs)

Production Example 158-11-{2-Chloro-4-[6-[4-(2S)-2-hydroxy-3-pyrrolidinopropoxy)phenyl]-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]phenyl}-3-cyclopropylurea

The title compound (30 mg) was obtained from 81 mg of1-{2-chloro-4-[6-(4-hydroxyphenyl)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]-2-phenyl}-3-cyclopropylurea,using 98 mg of (2S)-(+)-glycidyl p-toluenesulfonate, 99 mg of potassiumcarbonate and 0.1 ml of pyrrolidine, in the same manner as ProductionExample 153-9.

MS Spectrum (ESI): 693 (M+1),

¹H-NMR Spectrum: (DMSO-d₆) −0.09 (9H, s), 0.40-0.46 (2H, m), 0.62-0.70(2H, m), 0.87 (2H, t, J=8.4 Hz), 1.62-1.72 (4H, m), 2.40-2.68 (7H, m,covered by DMSO peak), 3.62 (2H, t, J=8.4 Hz), 3.90-4.10 (3H, m), 4.92(1H, brs), 5.60 (2H, s,) 6.72 (1H, s,), 7.10 (2H, d, J=8.8 Hz), 7.17(1H, d, J=2.4 Hz), 7.21 (1H, dd, J=2.4, 8.8 Hz), 7.46 (1H, d, J=2.4 Hz),7.71 (2H, d, J=8.8 Hz), 7.95 (1H, s), 8.18 (1H, d, J=8.8 Hz), 8.41 (1H,s)

Example 1591-(2-Chloro-4-{6-[4-((2R)-2-hydroxy-3-pyrrolidinopropoxy)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]phenyl}-3-cyclopropylurea

The title compound (24 mg) was obtained from 70 mg of1-{2-chloro-4-[6-[4-(2-hydroxy-3-pyrrolidinopropoxy)phenyl]-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]phenyl}-3-cyclopropylurea,in the same manner as Example 153.

MS Spectrum (ESI): 563 (M+1),

¹H-NMR Spectrum: (DMSO-d₆) 0.40-0.47 (2H, m), 0.60-0.70 (2H, m),1.73-1.87 (4H, m), 2.49-2.60 (7H, m, covered by DMSO peak), 3.94-4.19(3H, m), 4.92 (1H, brs) 6.94 (1H, d, J=1.2 Hz), 7.06 (2H, d, J=8.6 Hz),7.15-7.22 (2H, m), 7.43 (1H, d, J=2.4 Hz), 7.91 (2H, d, J=8.6 Hz), 7.96(1H, s), 8.17 (1H, d, J=8.6 Hz), 8.29 (1H, s) 12.61 (1H, brs)

Production Example 159-11-{2-Chloro-4-[6-[4-((2R)-2-hydroxy-3-pyrrolidinopropoxy)phenyl]-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]phenyl}-3-cyclopropylurea

The title compound (72 mg) was obtained from 128 mg of1-{2-chloro-4-[6-(4-hydroxyphenyl)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]phenyl}-3-cyclopropylurea,using 155 mg of (2R)-(−)-glycidyl p-toluenesulfonate, 156 mg ofpotassium carbonate and 0.13 ml of pyrrolidine, in the same manner asProduction Example 153-9.

MS Spectrum (ESI): 693 (M+1),

¹H-NMR Spectrum: (DMSO-d₆) −0.09 (9H, s), 0.40-0.46 (2H, m), 0.60-0.70(2H, m), 0.87 (2H, t, J=8.4 Hz), 1.62-1.72 (4H, m), 2.40-2.68 (7H, m,covered by DMSO peak), 3.61 (2H, t, J=8.4 Hz), 3.90-4.10 (3H, m), 4.92(1H, brs,), 5.60 (2H, s,), 6.72 (1H, s), 7.09 (2H, d, J=8.8 Hz), 7.16(1H, d, J=2.4 Hz), 7.20 (1H, dd, J=2.4, 8.8 Hz), 7.45 (1H, d, J=2.4 Hz),7.71 (2H, d, J=8.8 Hz), 7.95 (1H, s), 8.18 (1H, d, J=8.8 Hz), 8.40 (1H,s)

Example 1601-(2-Chloro-4-{6-[4-(2-diethylaminopropoxy)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy}phenyl)-3-cyclopropylurea

The title compound (2 mg) was obtained from 17 mg of1-{2-chloro-4-[6-[4-(2-diethylaminopropoxy)phenyl]-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]phenyl}-3-cyclopropylurea,in the same manner as Example 153.

MS Spectrum (ESI): 549 (M+1),

Production Example 160-14-[4-(4-Amino-3-chlorophenoxy)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenol

After dissolving 255 mg of the4-[6-(4-benzyloxyphenyl)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]-2-chlorophenylamine synthesized in Production Example 153-5 in 10 ml of ethanol and 3ml of tetrahydrofuran, 100 mg of platinum oxide was added and themixture was stirred overnight at room temperature under normal pressurein a hydrogen atmosphere. After filtering with celite, the filtrate wasconcentrated under reduced pressure. The residue was subjected to silicagel column chromatography (hexane-ethyl acetate) to obtain 105 mg of thetitle compound.

1H-NMR Spectrum: (DMSO-d₆) −0.09 (9H, s), 0.83 (2H, t, J=7.8 Hz), 3.52(2H, t, J=7.8 Hz), 5.33 (2H, s), 5.54 (2H, s), 6.55 (1H, s), 6.83 (1H,d, J=8.8 Hz), 6.88 (2H, d, J=8.8 Hz), 6.94 (1H, dd, J=2.4, 8.8 Hz), 7.17(1H, d, J=2.4 Hz), 7.58 (2H, d, J=8.8 Hz), 8.35 (1H, s), 9.84 (1H, brs)

Production Example 160-22-Chloro-4-[6-[4-(3-diethylaminopropoxy)phenyl]-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]phenylamine

After dissolving 47 mg of the4-[4-(4-amino-3-chlorophenoxy)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenolsynthesized in Production Example 160-1 in 0.5 ml of dimethylformamide,there were added 56 mg (3.1 equivalents) of (3-chloropropyl)diethylaminehydrochloride and 94 mg (7 equivalents) of potassium carbonate, and themixture was stirred at 80° C. for 24 hours. It was then returned to roomtemperature, water was added, and liquid separation and extraction wereperformed with an ethyl acetate:tetrahydrofuran (5:1) mixed solvent. Theorganic layer was dried over sodium sulfate, concentrated and subjectedto NH silica gel column chromatography (hexane-ethyl acetate) to obtain49 mg of the title compound.

Ms Spectrum (ESI): 596 (M+1),

Production Example 160-31-{2-Chloro-4-[6-[4-(3-diethylaminopropoxy)phenyl]-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]phenyl}-3-cyclopropylurea

After dissolving the2-chloro-4-[6-[4-(3-diethylaminopropoxy)phenyl]-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]phenylaminesynthesized in Production Example 160-2 in 0.6 ml of dimethylsulfoxide,23 mg of phenyl cyclopropylcarbamate was added and the mixture wasstirred at 80° C. for 1.5 hours. After further adding 75 mg of phenylN-cyclopropylcarbamate and stirring at 100° C. for 5 hours, 70 mg of thesame reagent was added prior to stirring overnight. The mixture was thenreturned to room temperature, water was added, and liquid separation andextraction were performed with an ethyl acetate:tetrahydrofuran (5:1)mixed solvent. The organic layer was dried over sodium sulfate,concentrated and subjected to NH silica gel column chromatography(hexane-ethyl acetate) to obtain 18 mg of the title compound.

MS Spectrum (ESI): 679 (M+1),

Example 1611-(4-Fluorophenyl)-3-[4-(6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylsulfanyl)thiazol-5-ylurea

After adding 323 mg of iron powder, 12 ml of ethanol and 2.4 ml of waterto 4-(5-nitrothiazol-2-ylsulfanyl)-6-phenyl-7H-pyrrolo[2,3-d]pyrimidine,the mixture was stirred at 80° C. for 10 minutes and then returned toroom temperature, after which 7.5 mg of potassium carbonate was added,the mixture was filtered with celite, and ethyl acetate and water wereadded to the filtrate for liquid separation and extraction. The organiclayer was washed with saturated brine, dried over anhydrous sodiumsulfate, filtered with plug cotton and concentrated to dryness to obtain310 mg of a solid. The solid was dissolved in 10 ml of tetrahydrofuran,10 ml of toluene and 10 ml of acetonitrile under reflux, and then 0.1 mlof 4-fluorophenyl isocyanate was added and the mixture was stirred for 2hours. It was then returned to room temperature, and the reaction systemwas concentrated, subjected to silica gel column chromatography anddried to obtain 33 mg of the title compound.

¹H-NMR Spectrum: (DMSO-d₆) 6.71 (1H, s,), 7.12 (2H, m), 7.36-7.52 (5H,m), 7.62 (1H, s), 7.92 (2H, d, J=8.1 Hz), 8.55 (1H, s), 9.12 (1H, s),10.24 (1H, s), 12.82 (1H, brs)

The intermediates were synthesized in the following manner.

Production Example 161-1 6-Phenyl-7H-pyrrolo[2,3-d]pyrimidine-4-thiol

After adding 6.19 g of phosphorus pentasulfide, 6.24 g of sodiumbicarbonate and 25 ml of diglyme to 2.45 g of the6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ol described in WO97/02266 andPCT/EP96/02728, and stirring the mixture for 1 hour, an additional 3 gof phosphorus pentasulfide and 3 g of sodium bicarbonate were added andthe mixture was stirred for 1 hour. There were further added another 3 gof phosphorus pentasulfide and 3 g of sodium bicarbonate, and themixture was stirred for 1 hour. It was then returned to roomtemperature, water was added, the mixture was stirred for 10 minutes,and the precipitated crystals were filtered out, washed with water anddried to obtain 2.5 g of the title compound.

¹H-NMR Spectrum: (DMSO-d₆) 7.05 (1H, d, J=2.1 Hz), 7.32 (1H, t, J=7.9Hz), 7.43 (2H, t, J=7.9 Hz), 7.88 (2H, d, J=7.9 Hz), 8.05 (1H, s), 12.68(1H, brs), 13.36 (1H, brs)

Production Example 161-24-(5-Nitrothiazol-2-ylsulfanyl)-6-phenyl-7H-pyrrolo[2,3-d]pyrimidine

After adding 1.06 g of 2-bromo-5-nitrothiazole and 15 ml ofdimethlforamide to 6-phenyl-7H-pyrrolo[2,3-d-]pyrimidine-4-thiol, themixture was stirred at room temperature for 3 hours, and then 0.45 ml ofpyridine was added and the mixture was stirred overnight. Water wasadded, and the precipitated crystals were filtered out, blow-dried anddried under reduced pressure to obtain 1.20 g of the title compound.

¹H-NMR Spectrum: (DMSO-d₆) 7.26 (1H, J=2.4 Hz), 7.36-7.54 (3H, m), 8.01(2H, d, J=7.8 Hz), 8.90 (1H, s,), 8.94 (1H, s,), 13.11 (1H, brs),

Example 1621-[5-(6-Phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylsulfanyl)-3-thiazol-2-ylurea

After adding 265 mg of phenyl 2-thiazoylcarbamate and ml ofdimethylsulfoxide to 354 mg of5-(6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylsulfanyl)-2-thiophenylamine,the mixture was stirred at 80° C. for 2 hours. Ethyl acetate and waterwere added for liquid separation and extraction, the organic layer wasconcentrated and subjected to silica gel column chromatography anddried, and the obtained solid was washed with ether to obtain 170 mg ofthe title compound.

¹H-NMR Spectrum: (DMSO-d₆) 6.55 (1H, brs), 6.94 (1H, d, J=4.2 Hz), 7.05(1H, d, J=1.9 Hz), 7.26 (1H, d, J=4.2 Hz), 7.28-7.50 (4H, m), 7.82-7.90(3H, m), 8.49 (1H, s), 10.42 (1H, brs), 12.54 (1H, brs)

The intermediates were synthesized in the following manner.

Production Example 162-14-(5-Nitro-2-thiophenylsulfanyl)-6-phenyl-7H-pyrrolo[2,3-d]pyrimidine

After adding 1.05 g of 2-bromo-5-nitrothiophene, 0.95 g of potassiumcarbonate and 15 ml of dimethylformamide to the6-phenyl-7H-pyrrolo[2,3-d]pyrimidine-4-thiol synthesized in ProductionExample 161-1 and stirring the mixture overnight at room temperature,water was added and the precipitated crystals were filtered out,blow-dried and dried under reduced pressure to obtain 1.30 g of thetitle compound.

¹H-NMR Spectrum: (DMSO-d₆) 7.08 (1H, s), 7.40 (1H, t, J=8.0 Hz), 7.48(2H, t, J=8.0 Hz), 7.56 (1H, d, J=4.1 Hz), 7.98 (2H, d, J=8.0 Hz), 8.16(1H, d, J=4.1 Hz), 8.70 (1H, s), 12.68 (1H, brs)

Production Example 162-25-(6-Phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylsulfanyl)-thiophen-2-ylamine

After adding 543 mg of iron powder, 1.06 g of ammonium chloride, 10 mlof dimethylformamide, 20 ml of ethanol and 5 ml of water to the4-(5-nitro-2-thiophenylsulfanyl)-6-phenyl-7H-pyrrolo[2,3-d]pyrimidinesynthesized in Production Example 162-1, the mixture was stirred at 90°C. for 2 hours, 30 ml of tetrahydrofuran was added, and then the mixturewas returned to room temperature and filtered with celite, and ethylacetate and water were added to the filtrate for liquid separation andextraction. The organic layer was dried over anhydrous sodium sulfate,filtered with plug cotton and concentrated to dryness to obtain 435 mgof the title compound.

MS Spectrum (ESI): 325 (M+1)

¹H-NMR Spectrum: (DMSO-d₆) 5.98 (1H, d, J=4.2 Hz), 6.24 (2H, s), 6.27(1H, d, J=2.0 Hz), 7.00 (1H, d, J=4.2 Hz), 7.30-7.50 (3H, m), 7.80 (2H,d, J=7.6 Hz), 8.46 (1H, s), 12.63 (1H, brs)

Example 1634-{4-[3-(4-Fluorophenyl)ureido]phenoxy)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid ethyl ester

After dissolving 90 mg of ethyl4-(4-aminophenoxy)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate in 3 ml oftoluene and 1 ml of acetonitrile at 110° C., 16.6 μl of 4-fluorophenylisocyanate was added and the mixture was stirred for 1 hour underreflux. After standing at room temperature, the precipitated crystalswere filtered out and dried to obtain 110 mg of the title compound.

¹H-NMR Spectrum: (DMSO-d₆) 1.31 (3H, t, J=7.9 Hz), 4.32 (2H, q, J=7.9Hz), 7.07-7.54 (9H, m), 8.42 (1H, s), 8.72 (1H, s), 8.76 (1H, s), 13.03(1H, brs)

The intermediates were synthesized in the following manner.

Production Example 163-14-(4-Nitrophenoxy)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid ethylester

After adding 390 mg of 4-nitrophenol, 703 mg of potassium carbonate and8.7 ml of dimethylformamide to 577 mg of the4-chloroethoxycarbonyl-7H-pyrrolo[2,3-d]pyrimidine described inWO9702266(A1) and stirring the mixture at 120° C. for 4 hours, 40 mg of4-nitrophenol was further added and the mixture was stirred for 1.5hours. After returning the mixture to room temperature, water was added,liquid separation and extraction were performed with an ethylacetate-tetrahydrofuran mixed solvent, and the organic layer was washedwith saturated brine, dried over anhydrous sodium sulfate, filtered withplug cotton and concentrated to dryness to obtain a solid which was thenwashed with ether to obtain 520 mg of the title compound.

¹H-NMR Spectrum: (DMSO-d₆) 1.33 (3H, t, J=7.9 Hz), 4.35 (2H, q, J=7.9Hz), 7.28 (1H, s), 7.56-7.64 (2H, m), 8.30-8.38 (2H, m), 8.46 (1H, s),13.21 (1H, brs)

Production Example 163-24-(4-Aminophenoxy)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid ethylester

After adding 110 mg of iron powder, 220 mg of ammonium chloride, 10 mlof ethanol and 2 ml of water to4-(4-nitrophenoxy)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid ethylester, the mixture was stirred at 80-85° C. for 2.5 hours. Afterreturning the mixture to room temperature, 20 ml of tetrahydrofuran wasadded, the mixture was stirred for 5 minutes and filtered with celite,and 100 ml of ethyl acetate and 50 ml of water were added to thefiltrate for liquid separation and extraction. The organic layer waswashed with saturated brine, dried over anhydrous sodium sulfate,filtered with plug cotton and concentrated to dryness to obtain 90 mg ofthe title compound.

¹H-NMR Spectrum: (DMSO-d₆) 1.31 (3H, t, J=7.9 Hz), 4.31 (2H, q, J=7.9Hz), 5.10 (2H, s), 6.56-6.62 (2H, m), 6.86-9.92 (3H, m), 8.40 (1H, s),12.98 (1H, brs)

Example 1644-{4-[3-(4-Fluorophenyl)ureido]phenoxy)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid

After adding 7 ml of ethanol, 7 ml of water and 31 mg of lithiumhydroxide monohydrate to 75 mg of the4-{4-[3-(4-fluorophenyl)ureido]phenoxy)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid ethyl ester synthesized in Example 163 and stirring the mixture at40-45° C. for 24 hours, it was neutralized with 2N HCl and concentratedto dryness to obtain 40 mg of the title compound.

¹H-NMR Spectrum: (DMSO-d₆) 6.83 (1H, s), 7.06-7.16 (2H, m), 7.19 (2H,m), 7.44-7.48 (2H, m), 7.51 (2H, d, J=8.0 Hz), 8.39 (1H, s), 8.72 (1H,s), 8.76 (1H, s), 12.88 (1H, brs)

Example 1654-{4-[3-(4-Fluorophenyl)ureido]phenoxyl}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic(4-methylpiperazin)amide

After adding 1 ml of dimethylformamide, 47 μl of triethylamine, 18.5 μlof diphenylphosphoryl azide and 8.2 μl of 1-methylpiperazine to 12 mg ofthe4-{4-[3-(4-fluorophenyl)ureido]phenoxy)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid synthesized in Example 164, the mixture was stirred overnight atroom temperature. Water was added, and the mixture was subjected toliquid separation and extraction with an ethyl acetate-tetrahydrofuranmixed solvent and to NH silica gel column chromatography (ethylacetate-methanol) to obtain 27 mg of the title compound.

¹H-NMR Spectrum: (DMSO-d₆) 2.18 (3H, s), 2.28-2.48 (4H, m), 3.58-3.70(4H, m), 6.56 (1H, s), 7.06-7.56 (8H, m), 8.36 (1H, d, J=1.7 Hz), 8.78(1H, s), 8.84 (1H, s), 12.67 (1H, brs)

Example 1664-{4-[3-(4-Fluorophenyl)ureido]phenoxy}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic[4-(3-aminopropyl)morpholin]amide

After adding 0.8 ml of dimethylformamide, 21 μl of triethylamine, 9.5 μlof diphenylphosphoryl azide (DPPA) and 6.5 μl of4-(3-aminopropyl)morpholine to 12 mg of the4-{4-[3-(4-fluorophenyl)ureido]phenoxy}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid synthesized in Production Example 164, the mixture was stirred atroom temperature for 2 days. Saturated aqueous ammonium chloridesolution was added, liquid separation and extraction were performed withan ethyl acetate-tetrahydrofuran mixed solvent, and the organic layerwas washed with saturated brine, dried over anhydrous sodium sulfate,filtered with plug cotton and concentrated to dryness to obtain 9 mg ofthe title compound.

MS Spectrum (ESI): 534 (M+1)

¹H-NMR Spectrum: (DMSO-d₆) 1.62-1.74 (2H, m), 2.20-2.42 (6H, m),2.88-2.98 (2H, m), 3.46-3.62 (4H, m), 7.06-7.56 (9H, m), 8.34 (1H, s),8.84-8.90 (2H, m), 12.68 (1H, brs)

Example 1671-(4-Fluorophenyl)-3-[4-(6-hydroxymethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl]urea

After adding 9 ml of tetrahydrofuran to 55 mg of the4-{4-[3-(4-fluorophenyl)ureido]phenoxy)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid ethyl ester synthesized in Example 163 and stirring the mixture, 25mg of lithium aluminum hydride was added at room temperature and themixture was stirred for 2 days. Water was then added, liquid separationand extraction were performed with an ethyl acetate-tetrahydrofuranmixed solvent, and the organic layer was filtered with celite andconcentrated to dryness to obtain 35 mg of the title compound.

MS Spectrum (ESI): 394 (M+1), 416 (M+23)

¹H-NMR Spectrum: (DMSO-d₆) 4.55 (2H, d, J=6.7 Hz), 5.32 (1H, t, J=6.7Hz), 6.84 (1H, s), 7.06-7.55 (8H, m), 8.22 (1H, s), 8.74 (1H, s), 8.76(1H, s), 12.11 (1H, brs)

Example 1681-(4-Fluorophenyl)-3-[4-(6-formyl-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl]urea

After adding 3 ml of chloroform and 50 mg of manganese dioxide to 18 mgof1-(4-fluorophenyl)-3-[4-(6-hydroxymethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl]urea,the mixture was stirred overnight at room temperature. Tetrahydrofuranand ethyl acetate were added to the reaction system, and the mixture wasfiltered with celite and concentrated to dryness to obtain 16 mg of thetitle compound.

¹H-NMR Spectrum: (DMSO-d₆) 6.82 (1H, s), 7.03-7.60 (8H, m), 8.46 (1H,s), 8.71 (1H, s), 8.75 (1H, s), 9.86 (1H, s), 13.08 (1H, brs)

Example 1691-(4-Fluorophenyl)-3-[4-(6-morpholin-4-ylmethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl]urea

After adding 0.5 ml of tetrahydrofuran, 10 μl of morpholine and 26 mg ofsodium triacetoxyborohydride to the1-(4-fluorophenyl)-3-[4-(6-formyl-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl]ureasynthesized in Example 168, the mixture was stirred overnight at roomtemperature. The reaction system was subjected to liquid separation andextraction with a tetrahydrofuran-ethyl acetate mixed solvent, and thendried over anhydrous sodium sulfate and concentrated to dryness toobtain 5 mg of the title compound.

MS Spectrum (ESI): 463 (M+1)

Example 1701-(4-Fluorophenyl)-3-{4-[6-(4-methyl-1-piperazylmethyl)-1-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]phenyl}urea

After adding 0.4 ml of tetrahydrofuran, 11 μl of 1-methylpiperazine and23 mg of sodium triacetoxyborohydride to the1-(4-fluorophenyl)-3-[4-(6-formyl-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl]ureasynthesized in Example 168, the mixture was stirred overnight at roomtemperature. The reaction system was subjected to liquid separation andextraction with a tetrahydrofuran-ethyl acetate mixed solvent, and thendried over anhydrous sodium sulfate and concentrated to dryness toobtain 5 mg of the title compound.

MS Spectrum (ESI): 476 (M+1)

Example 1711-(4-Fluorophenyl)-3-[4-(6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl]urea

After dissolving 40 mg of4-(6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenylamine in 4.5 ml oftoluene and 4.5 ml of acetonitrile at 110° C., 4-fluorophenylisocyanate(16.6 μl) was added and the mixture was stirred for 1 hour. Afterreturning the mixture to room temperature, the precipitated crystalswere filtered out and dried to obtain 37 mg of the title compound.

MS Spectrum (ESI): 440 (M+1), 462 (M+23)

¹H-NMR Spectrum: (DMSO-d₆) 7.02 (1H, s), 7.06-7.52 (11H, m), 7.94 (2H,d, J=8.0 Hz), 8.28 (1H, s), 8.77 (1H, s), 8.79 (1H, s), 12.68 (1H, brs)

The intermediates were synthesized in the following manner.

Production Example 171-14-(4-Nitrophenoxy)-6-phenyl-7H-pyrrolo[2,3-d]pyrimidine

After adding 123 mg of 4-nitrophenol, 136 mg of potassium carbonate and1.5 ml of dimethylformamide to 113 mg of the4-chloro-6-phenyl-7H-pyrrolo[2,3-d]pyrimidine described in WO97/02266and PCT/EP96/02728, and stirring the mixture for 15 hours at 130-135°C., and additional 60 mg of 4-nitrophenol and 75 mg of potassiumcarbonate were added and the mixture was stirred for 6 hours. Afterreturning the mixture to room temperature, water was added, liquidseparation and extraction were performed with an ethylacetate-tetrahydrofuran mixed solvent, and the solid obtained byconcentration to dryness was washed with ether to obtain 112 mg of thetitle compound.

¹H-NMR Spectrum: (DMSO-d₆) 7.13 (1H, s), 7.37 (1H, t, J=7.7 Hz), 7.47(2H, t, J=7.7 Hz), 7.56-7.61 (2H, m), 7.74-8.00 (2H, m), 8.30-8.38 (3H,m), 12.82 (1H, brs)

Production Example 171-24-(6-Phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenylamine

After adding 110 mg of iron powder, 220 mg of ammonium chloride, 10 mlof ethanol and 2 ml of water to 110 mg of4-(4-nitrophenoxy)-6-phenyl-7H-pyrrolo[2,3-d]pyrimidine, the mixture wasstirred at 80-85° C. for 2.5 hours. After returning the mixture to roomtemperature, 20 ml of tetrahydrofuran was added, and the mixture wasstirred for 5 minutes and filtered with celite, after which 100 ml ofethyl acetate and 50 ml of water were added to the filtrate for liquidseparation and extraction. The organic layer was washed with saturatedbrine, dried over anhydrous sodium sulfate, filtered with plug cottonand concentrated to dryness to obtain 90 mg of the title compound.

MS spectrum (ESI) m/z 303 (M+1)

¹H-NMR Spectrum: (DMSO-d₆) 5.04 (2H, brs) 6.57-6.61 (2H, m), 6.84-6.90(3H, m), 7.34 (1H, t, J=7.7 Hz), 7.45 (2H, t, J=7.7 Hz), 7.87 (2H, t,J=7.7 Hz), 8.26 (1H, s) 12.61 (1H, brs)

Example 1721-(3-Fluorophenyl)-3-[4-(6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl]urea

The title compound (24 mg) was obtained by reacting 3-fluorophenylisocyanate (14 μl) with 36 mg of4-(6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenylamine, in the samemanner as Example 171.

MS Spectrum (ESI): 440 (M+1), 462 (M+23)

¹H-NMR Spectrum: (DMSO-d₆) 7.02 (1H, s), 7.08-7.54 (11H, m), 7.94 (2H,d, J=8.0 Hz), 8.28 (1H s,), 8.88 (1H s,), 9.00 (1H, s,), 12.68 (1H, brs)

Example 1731-Cyclopropyl-3-[4-(6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl]urea

After adding 30 mg of phenyl cyclopropylcarbamate and 0.5 ml ofdimethylsulfoxide to 40 mg of4-(6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenylamine, the mixturewas stirred at 80° C. for 4 hours. The mixture was returned to roomtemperature, water was added, liquid separation and extraction wereperformed with ethyl acetate, and the solid obtained by concentration todryness was washed with ether to obtain 6 mg of the title compound.

¹H-NMR Spectrum: (DMSO-d₆) 0.30-0.40 (2H, m), 0.55-0.65 (2H, m),2.43-2.57 (1H, m, covered by DMSO peak), 6.20 (1H, brs), 6.60 (2H, d,J=8.90 Hz), 6.83 (1H, s), 6.87-6.91 (1H, m), 7.10-7.16 (1H, m),7.30-7.50 (3H, m), 7.90 (2H, d, J=8.1 Hz), 8.26 (1H, d, J=0.4 Hz), 8.92(1H, brs,), 12.60 (1H, brs)

Example 1741-[4-(6-Phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl]-3-(thiazol-2-yl)urea

After adding 492 mg of phenyl 2-thiazoylcarbamate to 520 mg of4-(6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenylamine, the mixturewas stirred at 80° C. for 4 hours. The precipitated crystals werefiltered out and washed with ethyl acetate and tetrahydrofuran to obtain275 mg of the title compound.

1H-NMR Spectrum: (DMSO-d₆) 7.03 (1H, d, J=2.0 Hz), 7.10 (1H, d, J=3.0Hz), 7.18-7.50 (7H, m), 7.54 (2H, d, J=8.7 Hz), 7.74 (2H, d, J=8.0 Hz),8.29 (1H s,), 9.10 (1H, s,), 12.69 (1H, brs)

Example 1751-(4-Fluorophenyl)-3-[2-fluoro-4-(6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl]urea

The title compound (26 mg) was obtained from 36 mg of2-fluoro-4-(6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenylamine, inthe same manner as Example 171.

¹H-NMR Spectrum: (DMSO-d₆) 7.05-7.18 (4H, m), 7.30-7.50 (6H, m), 7.94(2H, d, J=8.1 Hz), 8.21 (1H, t, J=10.4 Hz), 8.32 (1H, s), 8.55 (1H, d,J=1.9 Hz), 9.09 (1H, s), 12.73 (1H, brs)

The intermediates were synthesized in the following manner.

Production Example 175-14-(3-Fluoro-4-nitrophenoxy)-6-phenyl-7H-pyrrolo[2,3-d]pyrimidine

After adding 328 mg of 3-fluoro-4-nitrophenol, 0.22 ml of 2,6-lutidineand 0.9 ml of N-methylpyrrolidine to 360 mg of the4-chloro-6-phenyl-7H-pyrrolo[2,3-d]pyrimidine described in WO97/02266and PCT/EP96/02728 and stirring the mixture overnight at 130° C., it wasreturned to room temperature, water was added, the precipitated solidwas filtered out and washed with water and diethyl ether, and thecollected solid was dried to obtain 112 mg of the title compound.

¹H-NMR Spectrum: (DMSO-d₆) 7.14 (1H, s), 7.34-7.44 (2H, m), 7.48 (2H, t,J=7.8 Hz), 7.73 (1H, dd, J=2.5 Hz, 11.8 Hz), 7.89 (2H, d, J=7.8 Hz),8.28 (1H, t, J=8.5 Hz), 8.40 (1H, d, J=1.3 Hz), 12.87 (1H, brs)

Production Example 175-24-(6-Phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenylamine

The title compound (118 mg) was obtained from 125 mg of the4-(3-fluoro-4-nitrophenoxy)-6-phenyl-7H-pyrrolo[2,3-d]pyrimidinesynthesized by the intermediate synthesis method described above, in thesame manner as Production Example 171-2.

¹H-NMR Spectrum: (DMSO-d₆) 5.10 (2H, s), 6.78-7.04 (4H, m), 7.37 (1H, t,J=7.9 Hz), 7.47 (2H, t, J=7.9 Hz), 7.92 (2H, d, J=7.9 Hz), 8.38 (1H, s),12.67 (1H, brs)

Example 1761-(3-Fluorophenyl)-3-[2-fluoro-4-(6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl]urea

The title compound (27 mg) was obtained from 33 mg of2-fluoro-4-(6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenylamine, inthe same manner as Example 171.

¹H-NMR Spectrum: (DMSO-d₆) 6.78 (1H, dt, J=3.3, 9.5 Hz), 7.06-7.52 (8H,m), 7.97 (2H, t, J=8.2 Hz), 8.11 (1H, t, J=9.5 Hz), 8.42 (1H, s), 8.62(1H, s), 8.62 (1H, s), 9.28 (1H, s), 12.73 (1H, brs)

Example 1771-[2-Fluoro-4-(6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl]-3-(thiazol-2-yl)urea

The title compound (27 mg) was obtained from 42 mg of2-fluoro-4-(6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenylamine, inthe same manner as Example 171.

¹H-NMR Spectrum: (DMSO-d₆) 7.06-7.16 (3H, m), 7.12-7.44 (3H, m), 7.47(2H, t, J=8.1 Hz), 7.96 (2H, d, J=8.1 Hz), 8.12 (1H, t, J=9.1 Hz), 8.32(1H, s), 8.96 (1H, brs), 10.78 (1H, brs), 12.73 (1H, brs)

Example 1785-[6-(4-Hydroxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]indole-1-carboxylicethylamide

After dissolving 30 mg of5-[6-(4-benzyloxyphenyl)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]indole-1-carboxylicethylamide in 1 ml of trifluoroacetic acid and 0.1 ml of thioanisole,the mixture was stirred at 50-55° C. The mixture was then returned toroom temperature, saturated sodium bicarnobate water was added toalkalinity, and liquid separation and extraction were performed with anethyl acetate-tetrahydrofuran (5:1) mixed solvent. The organic layer wasconcentrated, 1 ml of tetrahydrofuran and 1 ml of 2N aqueous sodiumhydroxide were added to the residue, and the mixture was stirred at roomtemperature for 5 minutes. After neutralization with 1N hydrochloricacid, liquid separation and extraction were performed with an ethylacetate-tetrahydrofuran (5:1) mixed solvent. The organic layer wasconcentrated and the residue was subjected to silica gel columnchromatography (hexane-ethyl acetate) to obtain 5 mg of the titlecompound.

MS Spectrum (ESI): 468 (M+55); (M+Na+MeOH)

¹H-NMR Spectrum: (DMSO-d₆) 1.18 (3H, t, J=6.7 Hz), 3.20-3.50 (2H, m,covered by H2O peak), 6.67 (1H, d, J=3.5 Hz), 6.78 (1H, s,), 6.83 (2H,d, J=8.4 Hz), 7.12 (1H, dd, J=2.2, 8.4 Hz), 7.44 (1H, d, J=2.2 Hz), 7.74(2H, d, J=8.4 Hz), 7.89 (1H, d, J=3.3 Hz), 8.16-8.22 (2H, m), 8.25 (1H,d, J=8.4 Hz), 9.80 (1H, brs,), 12.45 (1H, brs),

Example 1796-(4-Benzyloxyphenyl)-4-(1H-5-indolyloxy)-7H-pyrrolo[2,3-d]pyrimidine

After dissolving 1.5 ml of tetrahydrofuran in 22 mg of5-[6-(4-benzyloxyphenyl)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]-indole-1-carboxylicethylamide, a 1M solution of tetrabutylammonium fluoride intetrahydrofuran was added and the mixture was refluxed for 2 hours.After returning it to room temperature, water was added and theprecipitated crystals were filtered out and subjected to silica gelcolumn chromatography (hexane-ethyl acetate) to obtain 2 mg of the titlecompound.

¹H-NMR Spectrum: (DMSO-d₆) 5.17 (2H, s), 6.40-6.43 (1H, m), 6.80 (1H,s,), 6.93 (1H, dd, J=2.5, 8.8 Hz), 7.10 (2H, d, J=8.8 Hz), 7.30-7.50(8H, m), 7.83 (2H, d, J=8.8 Hz), 8.20 (1H, s), 11.19 (1H, brs), 12.51(1H, brs),

The intermediates were synthesized in the following manner.

Production Example 179-16-(4-Benzyloxyphenyl)-4-(1H-5-indolyloxy)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine

After adding 1.9 ml of dimethylformamide, 180 mg of 5-hydroxyindole and112 mg of potassium carbonate to 190 mg of6-(4-benzyloxyphenyl)-4-chloro-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine,the mixture was stirred at 135-140° C. for 4 hours. After returning itto room temperature, water was added, and liquid separation andextraction were performed with an ethyl acetate:tetrahydrofuran (5:1)mixed solvent. The organic layer was concentrated and subjected to NHsilica gel column chromatography (hexane-ethyl acetate) to obtain 90 mgof the title compound.

MS Spectrum (ESI): 563 (M+1)

¹H-NMR Spectrum: (DMSO-d₆) −0.09 (9H, s), 0.87 (2H, t, J=8.4 Hz), 3.62(2H, t, J=8.4 Hz) 5.19 (2H, s), 5.59 (2H, s), 6.42-6.46 (1H, m), 6.65(1H, s), 6.83 (2H, d, J=8.4 Hz), 6.97 (1H, dd, J=2.6, 8.6 Hz), 7.16 (2H,d, J=8.6 Hz), 7.32-7.50 (8H, m), 7.70 (2H, d, J=8.6 Hz), 8.37 (1H, d,J=1.7 Hz), 11.21 (1H, brs).

Production Example 179-25-[6-(4-Benzyloxyphenyl)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]indole-1-carboxylicethylamide

After dissolving6-(4-benzyloxyphenyl)-4-(1H-5-indolyloxy)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine(81 mg) in 1 ml of dimethylformamide, 7 mg of sodium hydride (60%dispersion) was added, the mixture was stirred at room temperature for 5minutes, and then 31 mg of phenyl ethylcarbamate was added and themixture was stirred for another 2 hours. Water was then added, and ethylacetate was used for liquid separation and extraction. The organic layerwas concentrated and subjected to silica gel column chromatography(hexane-ethyl acetate) to obtain 62 mg of the title compound.

MS Spectrum (ESI): 634 (M+1), 688 (M+55); (M+Na+MeOH)

¹H-NMR Spectrum: (DMSO-d₆) −0.09 (9H, s,), 0.87 (3H, t, J=8.5 Hz), 1.20(2H, t, J=6.7 Hz), 3.10-3.70 (4H, m, covered by H2O peak), 5.20 (2H, s),5.60 (2H, s), 6.67 (1H, s), 6.70 (1H, d, J=3.8 Hz), 7.12-7.20 (3H, m),7.30-7.52 (6H, m), 7.72 (2H, d, J=9.0 Hz), 7.91 (1H, d, J=3.8 Hz), 8.23(1H, t, J=5.9 Hz), 8.29 (1H, d, J=9.0 Hz), 8.38 (1H, s)

Example 180N-[4-(2-Cyclopropyl-3-methylimidazo[4,5-b]pyridin-4-yl)oxyphenyl]-N′-(4-fluorophenyl)urea

N-[4-(2-Cyclopropyl-3H-imidazo[4,5-b]pyridin-4-yl)oxyphenyl]-N′-(4-fluorophenyl)urea(25 mg), iodomethane (13 mg), potassium carbonate (26 mg) anddimethylformamide (5 ml) were stirred at 70° C. for 20 minutes. Waterwas added, extraction was performed with ethyl acetate, and then silicagel was added to the extract and the solvent was distilled off underreduced pressure. The silica gel was charged into a dry column packedwith silica gel and purified by column chromatography (ethyl acetate,followed by ethyl acetate:methanol=10:1) to obtain 3 mg of the targetsubstance as a white powder.

¹H-NMR(CDCl₃) δ (ppm): 1.13-1.19 (2H, m), 1.28-1.35 (2H, m), 2.03-2.11(1H, m), 3.95 (3H, s), 6.43 (1H, d, J=5.6 Hz), 6.95-7.04 (4H, m),7.26-7.35 (4H, m), 8.19 (1H, d, J=5.6 Hz).

Example 181N-[4-(2-Butylaminopyridin-4-yl)oxyphenyl]-N′-(4-fluorophenyl)urea

4-(4-Aminophenoxy)-2-butylaminopyridine (54 mg), p-fluorophenylisocyanate (34.5 mg) and tetrahydrofuran (5 ml) were stirred at roomtemperature for 2.5 hours. After adding NH type silica gel to thereaction solution, the solvent was distilled off under reduced pressure,and the reaction product was adsorbed onto the silica gel. The silicagel was charged into a dry column packed with NH type silica gel, andcolumn purification was performed (hexane:ethyl acetate=1:1, followed byethyl acetate). The solvent was distilled off under reduced pressure andthe residue was solidified with ethyl acetate-hexane to obtain 15 mg ofthe target substance as a light yellow powder.

¹H-NMR (DMSO-d₆) δ (ppm): 0.87 (3H, t, J=7.2 Hz), 1.30 (2H, tq, J=7.2Hz, 7.2 Hz), 1.44 (2H, tt, J=7.2 Hz, 7.2 Hz), 3.16 (2H, q, J=7.2 Hz),5.80 (1H, d, J=2.0 Hz), 6.09 (1H, ddd, J=5.0 Hz, 2.0 Hz, 2.0 Hz), 6.45(1H, dd, J=5.0 Hz, 5.0 Hz), 7.03-7.18 (4H, m), 7.43-7.55 (4H, m), 7.83(1H, dd, J=5.0 Hz, 2.0 Hz), 8.70 (1H, s), 8.74 (1H, s).

The intermediate was synthesized in the following manner.

Production Example 181-1 4-(4-Aminophenoxy)-2-butylaminopyridine

After dissolving 80 mg of 4-(4-aminophenoxy)-2-butyrylaminopyridine in 8ml of tetrahydrofuran, 67 mg of lithium aluminum hydride was added whilestirring at room temperature, and the mixture was stirred at 70° C. for10 minutes. Water was added, extraction was performed with ethylacetate, and then silica gel was added to the extract and the solventwas distilled off under reduced pressure. The silica gel was chargedinto a dry column packed with silica gel and purified by columnchromatography (ethyl acetate) to obtain 54 mg of the target substanceas a brown oil.

¹H-NMR(CDCl₃) δ (ppm): 0.93 (3H, t, J=7.2 Hz), 1.40 (2H, tq, J=7.2 Hz,7.2 Hz), 1.56 (2H, tt, J=7.2 Hz, 7.2 Hz), 3.14 (2H, q, J=7.2 Hz), 5.82(1H, d, J=2.0 Hz), 6.14 (1H, dd, J=6.0 Hz, 2.0 Hz), 6.66-6.74 (2H, m),6.86-6.94 (2H, m), 7.87 (1H, d, J=6.0 Hz).

Example 182N-(4-Fluorophenyl)-N′-{4-[(7-oxo-5,6,7,8-tetrahydro[1,8]naphthyridin-4-yl)oxy]phenyl}urea

4-[(7-Oxo-5,6,7,8-tetrahydro[1,8]naphthyridin-4-yl)oxy]aniline (43 mg),p-fluorophenyl isocyanate (28 mg), tetrahydrofuran (5 ml) anddimethylformamide (2 ml) were stirred at room temperature for 30minutes. Water was added dropwise at room temperature untilprecipitation of crystals, and these were filtered out to obtain 48 mgof the target substance as white crystals.

¹H-NMR (DMSO-d₆) δ (ppm): 2.50 (2H, t, J=8.0 Hz), 2.91 (2H, t, J=8.0Hz), 6.24 (1H, d, J=6.0 Hz), 7.03-7.35 (4H, m), 7.40-7.55 (4H, m), 7.94(1H, d, J=6.0 Hz), 8.70 (1H, s), 8.74 (1H, s), 10.48 (1H, s).

The intermediates were synthesized in the following manner.

Production Example 182-1 4-Chloro-3-iodo-2-pyridinamine

A solution of 10 g of the publicly known compound tert-butylN-(4-chloro-2-pyridyl)carbamate, 16.6 ml ofN,N,N′,N′-tetramethylethylenediamine and 200 ml of tetrahydrofuran wascooled to −75° C., and then 42 ml of n-butyllithium (2.6M solution inhexane) was added dropwise over a period of 30 minutes while stirring.After stirring for 1 hour at −75° C., a solution of 28 g of iodine in 28ml of tetrahydrofuran was added dropwise over a period of 30 minutes.After completion of the dropwise addition, stirring was continued foranother 30 minutes at −75° C., and then the mixture was returned to roomtemperature, aqueous sodium bisulfate was added and extraction wasperformed with ethyl acetate. NH type silica gel was added to theextract, the solvent was distilled off under reduced pressure, and thereaction product was adsorbed onto the silica gel. The silica gel wascharged into a dry column packed with NH type silica gel, and columnpurification was performed (hexane:ethyl acetate=3:1). The solvent wasdistilled off under reduced pressure, 48% HBr water was added to theresidue, and the mixture was stirred at 100° C. for 5 minutes. Afteradding ice water and 5 N sodium hydroxide water to the reactionsolution, the precipitated solid was filtered out to obtain 7.4 g of alight yellow solid.

¹H-NMR (DMSO-d₆) δ (ppm): 6.50 (2H, bs), 6.72 (1H, d, J=5.6 Hz), 7.82(1H, d, J=5.6 Hz).

Production Example 182-2 3-Iodo-4-(4-nitrophenoxy)-2-pyridinamine

4-Chloro-3-iodo-2-pyridinamine (1.0 g), p-nitrophenol (1.1 g),diisopropylethylamine (1.0 ml) and N-methyl-2-pyrrolidone (2 ml) werestirred at 170° C. for 17 hours. After returning the reaction solutionto room temperature, water was added and extraction was performed withethyl acetate. NH type silica gel was added to the extract, the solventwas distilled off under reduced pressure, and the reaction product wasadsorbed onto the silica gel. The silica gel was charged into a drycolumn packed with NH type silica gel, and column purification wasperformed (hexane:ethyl acetate=3:1). The solvent was distilled offunder reduced pressure, and then ethyl acetate and hexane were added tothe residue for solidification to obtain 540 mg of light yellowcrystals.

¹H-NMR (DMSO-d₆) δ (ppm): 6.22 (1H, d, J=5.2 Hz), 6.37 (2H, brs), 7.19(2H, d, J=9.2 Hz), 7.87 (1H, d, J=5.2 Hz), 8.26 (2H, d, J=9.2 Hz).

Production Example 182-3 Ethyl(E)-3-[2-amino-4-(4-nitrophenoxy)-3-pyridyl]-2-propenoate

3-Iodo-4-(4-nitrophenoxy)-2-pyridinamine (500 mg), ethyl acrylate (0.3ml), palladium (II) acetate (30 mg), tributylamine (0.66 ml) anddimethylformaldehyde (5 ml) were stirred at 130° C. for 20 minutes.After returning the reaction solution to room temperature, water wasadded and extraction was performed with ethyl acetate. NH type silicagel was added to the extract, the solvent was distilled off underreduced pressure, and the reaction product was adsorbed onto the silicagel. The silica gel was charged into a dry column packed with NH typesilica gel, and column purification was performed (hexane:ethylacetate=3:1). The solvent was distilled off under reduced pressure toobtain 330 mg of the target substance as a yellow oil.

¹H-NMR(CDCl₃) δ (ppm): 1.31 (3H, t, J=7.2 Hz), 4.25 (2H, q, J=7.2 Hz),5.01 (2H, s), 6.18 (1H, d, J=6.0 Hz), 6.57 (1H, d, J=16 Hz), 7.12-7.19(2H, m), 7.73 (1H, d, J=16 Hz), 7.99 (1H, d, J=6.0 Hz), 8.24-8.32 (2H,m).

Production Example 182-44-[(7-Oxo-5,6,7,8-tetrahydro[1,8]naphthyridin-4-yl)oxy]aniline

Ethyl (E)-3-[2-amino-4-(4-nitrophenoxy)-3-pyridyl]-2-propenoate (330mg), palladium-carbon (10%, aqueous, 100 mg), methanol (5 ml) andtetrahydrofuran (5 ml) were stirred overnight at under a hydrogenatmosphere at 1 atmosphere. The palladium-carbon was filtered off, thefiltrate was distilled off under reduced pressure, and then the residuewas purified by silica gel column chromatography (ethyl acetate,followed by ethyl acetate:methanol=5:1) to obtain 43 mg of a whitesolid.

¹H-NMR (DMSO-d₆) δ (ppm): 2.49 (2H, t, J=8.0 Hz), 2.89 (2H, t, J=8.0Hz), 5.09 (2H, s), 6.15 (1H, dd J=6.0 Hz, 2.0 Hz), 6.58 (2H, dd, J=8.4Hz, 2.0 Hz), 6.79 (2H, dd, J=8.4 Hz, 2.0 Hz), 7.89 (1H, dd, J=6.0 Hz,2.0 Hz), 10.38 (1H, s).

Example 183N-(4-Fluorophenyl)-N′-{4-[(7-oxo-7,8-dihydro[1,8]naphthyridin-4-yl)oxy]phenyl}urea

N-(4-Fluorophenyl)-N′-{4-[(7-oxo-7,8-dihydro[1,8]naphthyridin-4-yl)oxy]aniline(30 mg), p-fluorophenyl isocyanate (0.016 ml) and dimethylformamide (6ml) were stirred at 70° C. until disappearance of the startingmaterials. After returning the reaction solution to room temperature,water was added dropwise and the precipitated solid was filtered out toobtain 22 mg of a light brown solid.

¹H-NMR (DMSO-d₆) δ (ppm): 6.35 (1H, d, J=5.6 Hz), 6.54 (1H, d, J=10 Hz),7.05-7.20 (4H, m), 7.40-7.60 (4H, m), 8.14 (1H, d, J=10 Hz), 8.29 (1H,d, J=5.6 Hz), 8.70 (1H, s), 8.78 (1H, s), 12.13 (1H, s).

The intermediates were synthesized in the following manner.

Production Example 183-14-(4-Nitrophenoxy)-7-oxo-7,8-dihydro[1,8]naphthyridine

Ethyl (E)-3-[2-amino-4-(4-nitrophenoxy)-3-pyridyl]-2-propenoate (350mg), 2′-acetonaphthone (50 mg) and methanol (80 ml) were irradiated for4 hours while stirring, and the precipitated solid was filtered out toobtain 156 mg of a light yellow solid.

¹H-NMR (DMSO-d₆) δ (ppm): 6.57 (1H, d, J=9.6 Hz), 6.70 (1H, d, J=5.6Hz), 7.46 (2H, d, J=8.0 Hz), 8.05 (1H, d, J=9.6 Hz), 8.33 (2H, d, J=8.0Hz), 8.42 (1H, d, J=5.6 Hz), 12.31 (1H, s).

Production Example 183-24-[(7-Oxo-7,8-dihydro[1,8]naphthyridin-4-yl)oxy]aniline

4-(4-Nitrophenoxy)-7-oxo-7,8-dihydro[1,8]naphthyridine (156 mg), ironpowder (300 mg), ammonium chloride (600 mg), dimethylformamide (2 ml),ethanol (1 ml) and water (1 ml) were stirred at 100° C. for 20 minutes.The mixture was filtered with celite, and then water and ethyl acetatewere added for extraction. The organic layer was washed 4 times withaqueous ammonium chloride solution and then dried over magnesiumsulfate. The drying agent was filtered off and the solvent was distilledoff under reduced pressure to obtain 30 mg of the target substance as alight yellow solid.

¹H-NMR (DMSO-d₆) δ (ppm): 5.19 (2H, brs), 6.29 (1H, d, J=5.6 Hz), 6.51(1H, d, J=9.6 Hz), 6.30 (2H, d, J=8.0 Hz), 6.87 (2H, d, J=8.0 Hz), 8.12(1H, d, J=9.6 Hz), 8.25 (1H, d, J=5.6 Hz), 12.10 (1H, s).

Example 184 Ethyl(E)-3-[2-[(cyclopropylcarbonyl)amino]-4-(4-{[(4-fluoroanilino)carbonyl]amino}phenoxy)-3-pyridyl]-2-propenoate

Ethyl(E)-3-[2-amino-4-(4-{[(4-fluoroanilino)carbonyl]amino}phenoxy)-3-pyridyl]-2-propenoate(200 mg), cyclopropanecarbonyl chloride (58 mg), triethylamine (0.1 m),tetrahydrofuran (4 ml) and dimethylformamide (1 ml) were stirred at roomtemperature for 20 minutes. A small amount of water was added dropwiseand the precipitated solid was filtered out to obtain 130 mg of a faintyellow solid.

¹H-NMR (DMSO-d₆) δ (ppm): 0.74 (4H, m), 1.21 (3H, t, J=7.2 Hz),1.88-1.95 (1H, m), 4.14 (2H, q, J=7.2 Hz), 6.53 (1H, d, J=5.6 Hz), 6.90(1H, d, J=16 Hz), 7.07-7.19 (4H, m), 7.40-7.48 (3H, m), 7.55 (2H, d,J=8.0 Hz), 8.21 (1H, d, J=5.6 Hz), 8.72 (1H, s), 8.81 (1H, s), 10.61(1H, s).

The intermediates were obtained in the following manner.

Production Example 184-1 Ethyl(E)-3-[2-amino-4-(4-aminophenoxy)-3-pyridyl]-2-propenoate

Ethyl (E)-3-[2-amino-4-(4-nitrophenoxy)-3-pyridyl]-2-propenoate (350mg), iron powder (700 mg), ammonium chloride (1.4 g), dimethylformamide(7 ml), ethanol (2 ml) and water (2 ml) were stirred at 100° C. for 20minutes. The mixture was filtered with celite, and then water and ethylacetate were added for extraction. The organic layer was washed 5 timeswith aqueous ammonium chloride solution and then dried over magnesiumsulfate. The drying agent was filtered off and the solvent was distilledoff under reduced pressure to obtain 230 mg of the target substance as alight yellow solid.

¹H-NMR(CDCl₃) δ (ppm): 1.33 (3H, t, J=7.2 Hz), 3.68 (2H, brs), 4.26 (2H,q, J=7.2 Hz), 4.87 (2H, bs), 6.02 (1H, d, J=6.0 Hz), 6.68 (1H, d, J=16Hz), 6.70 (2H, d, J=8.8 Hz), 6.87 (2H, d, J=8.8 Hz), 7.82 (1H, d, J=6.0Hz), 7.85 (1H, d, J=16 Hz).

Production Example 184-2 Ethyl(E)-3-[2-amino-4-(4-{[(4-fluoroanilino)carbonyl]amino}phenoxy)-3-pyridyl]-2-propenoate

Ethyl(E)-3-[2-amino-4-(4-aminophenoxy)-3-pyridyl]-2-propenoate (230 mg),p-fluorophenyl isocyanate (0.11 ml) and tetrahydrofuran (6 ml) werestirred at room temperature for 30 minutes. After adding NH type silicagel to the reaction solution, the solvent was distilled off underreduced pressure, and the reaction product was adsorbed onto the silicagel. The silica gel was charged into a dry column packed with NH typesilica gel, and column purification was performed (ethyl acetate). Thesolvent was distilled off under reduced pressure to obtain 200 mg of awhite solid.

¹H-NMR (DMSO-d₆) δ (ppm): 1.22 (3H, t, J=7.2 Hz), 4.14 (2H, q, J=7.2Hz), 5.83 (1H, d, J=5.6 Hz), 6.41 (2H, brs), 6.62 (1H, d, J=16 Hz),7.04-7.14 (4H, m), 7.40-7.53 (4H, m), 7.72 (1H, d, J=16 Hz), 7.79 (1H,d, J=5.6 Hz), 8.69 (1H, s), 8.75 (1H, s).

Example 185N-(4-Fluorophenyl)-N′-[4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]urea

After dissolving 90 mg of 4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)aniline inethyl acetate at room temperature, 0.05 ml of parafluorophenylisocyanate was added dropwise. The precipitated white crystals werefiltered out to obtain 65 mg of the target substance.

¹H-NMR (DMSO-d₆) δ (ppm): 6.21 (1H, d, J=3.6 Hz), 6.38 (1H, d, J=5.6Hz), 7.08-7.18 (4H, m), 7.34 (1H, d, J=3.6 Hz), 7.43-7.56 (4H, m), 8.06(1H, d, J=5.6 Hz), 8.72 (1H, s), 8.76 (1H, s), 11.72 (1H, s).

The intermediates were obtained in the following manner.

Production Example 185-14-(4-Nitrophenoxy)-3-[2-(1,1,1-trimethylsilyl)-1-ethynyl]-2-pyridineamine

4-(4-Nitrophenoxy)-3-iodo-pyridineamine (1.5 g),(trimethylsilyl)acetylene (1.5 ml),tetrakis(triphenylphosphine)palladium(0) (480 mg), copper (I) iodide (80mg), dimethylformamide (3 ml) and triethylamine (3 ml) were stirred at100° C. for 35 minutes. After returning the mixture to room temperature,water was added and extraction was performed with ethyl acetate. NH typesilica gel was added to the extract, the solvent was distilled off underreduced pressure, and the reaction product was adsorbed onto the silicagel. The silica gel was charged into a dry column packed with NH typesilica gel, and column purification was performed (hexane:ethylacetate=4:1). The solvent was distilled off under reduced pressure, andethyl acetate and hexane were added to the residue for solidification toobtain 560 mg of the target substance as a faint brown powder.

¹H-NMR (DMSO-d₆) δ (ppm): 0.30 (9H, s), 6.60 (1H, d, J=5.6 Hz), 6.67(2H, brs), 7.47 (2H, d, J=8.0 Hz), 8.24 (1H, d, J=5.6 Hz), 8.52 (2H, d,J=8.0 Hz).

Production Example 185-2 4-(4-Nitrophenoxy)-1H-pyrrolo[2,3-b]pyridine

4-(4-Nitrophenoxy)-3-[2-(1,1,1-trimethylsilyl)-1-ethynyl]-2-pyridinamine(560 mg), copper (I) iodide (680 mg) and dimethylformamide (5 ml) werestirred for 25 minutes under reflux. After filtering out the insolubleportion, NH type silica gel was added to the reaction solution, thesolvent was distilled off under reduced pressure, and the reactionproduct was adsorbed onto the silica gel. The silica gel was chargedinto a dry column packed with NH type silica gel, and columnpurification was performed (hexane:ethyl acetate=2:1, followed by 1:1).The solvent was distilled off under reduced pressure to obtain 84 mg ofa light yellow solid.

¹H-NMR (DMSO-d₆) δ (ppm): 6.14 (1H, d, J=3.6 Hz), 6.78 (1H, d, J=5.2Hz), 7.28 (2H, d, J=9.2 Hz), 7.43 (1H, d, J=3.6 Hz), 8.21 (1H, d, J=5.2Hz), 8.27 (2H, d, J=9.2 Hz), 11.92 (1H, brs).

Production Example 185-3 4-(1H-Pyrrolo[2,3-b]pyridin-4-yloxy)aniline

4-(4-Nitrophenoxy)-1H-pyrrolo[2,3-b]pyridine (84 mg), iron powder (160mg), ammonium chloride (320 mg), dimethylformamide (4 ml), ethanol (2ml) and water (2 ml) were stirred at 100° C. for 15 minutes. The mixturewas filtered with celite, and then water and ethyl acetate were addedfor extraction. The organic layer was washed 5 times with aqueousammonium chloride solution and then dried over magnesium sulfate. Thedrying agent was filtered off and the solvent was distilled off underreduced pressure to obtain 230 mg of the target substance as a brownoil.

¹H-NMR(CDCl₃) δ (ppm): 6.41 (1H, d, J=3.6 Hz), 6.42 (1H, d, J=5.6 Hz),6.74 (2H, d, J=8.8 Hz), 7.00 (2H, d, J=8.8 Hz), 7.20 (1H, d, J=3.6 Hz),8.11 (1H, d, J=5.6 Hz), 10.00 (1H, brs).

Example 186N1-Cyclopropylcarbonyl-N1-[3-(1-ethynyl)-4-(4-{[(4-fluoroanilino)carbonyl]amino}phenoxy)-2-pyridyl]-1-cyclopropanecarboxamide

After adding 57 mg of cyclopropanecarbonyl chloride to a solution ofN-(4-{[2-amino-3-(1-ethynyl)-4-pyridyl]oxy}phenyl)-N′-(4-fluorophenyl)urea(100 mg), triethylamine (0.12 ml) and tetrahydrofuran (5 ml) whilestirring at room temperature, stirring was continued for 1.5 hours.After adding NH type silica gel to the reaction solution, the solventwas distilled off under reduced pressure, and the reaction product wasadsorbed onto the silica gel. The silica gel was charged into a drycolumn packed with NH type silica gel, and column purification wasperformed (ethyl acetate). The organic solvent was distilled off underreduced pressure, and methanol and water were added to the residue forsolidification to obtain 15 mg of the target substance as a whitepowder.

¹H-NMR (DMSO-d₆) δ (ppm): 0.97-1.03 (8H, m), 1.93-2.02 (2H, m), 4.75(1H, s), 6.74 (1H, d, J=5.6 Hz), 7.08-7.20 (4H, m), 7.42-7.49 (2H, m),7.56 (2H, d, J=8.8 Hz), 8.35 (1H, d, J=5.6 Hz), 8.72 (1H, s), 8.81 (1H,s).

The intermediates were obtained in the following manner.

Production Example 186-13-(1-Ethynyl)-4-(4-nitrophenoxy)-2-pyridineamine

4-(4-Nitrophenoxy)-3-[2-(1,1,1-trimethylsilyl)-1-ethynyl]-2-pyridineamine(560 mg), tetrabutylammonium fluoride (1.0 M solution intetrahydrofuran, 1 ml) and tetrahydrofuran (2 ml) were stirred at roomtemperature for 10 minutes. Aqueous ammonium chloride solution and ethylacetate were added for extraction, and the extract was passed through aglass filter coated with silica gel. The silica gel was thoroughlywashed with ethyl acetate and the ethyl acetate was distilled off underreduced pressure to obtain 400 mg of the target substance as a brownpowder.

¹H-NMR (DMSO-d₆) δ (ppm): 4.52 (1H, s), 6.23 (1H, d, J=5.6 Hz), 6.46(2H, brs), 7.24 (2H, d, J=7.2 Hz), 7.94 (1H, d, J=5.6 Hz), 8.27 (2H, d,J=7.2 Hz).

Production Example 186-2 4-(4-Aminophenoxy)-3-(1-ethynyl)-2-pyridinamine

3-(1-Ethynyl)-4-(4-nitrophenoxy)-2-pyridinamine (400 mg), iron powder(800 mg), ammonium chloride (1.6 g), dimethylformamide (3 ml), ethanol(1 ml) and water (1 ml) were stirred at 100° C. for 30 minutes. Themixture was filtered with celite, and then water and ethyl acetate wereadded to the filtrate for extraction. The organic layer was washed 5times with aqueous ammonium chloride solution and then dried overmagnesium sulfate. The drying agent was filtered off and the solvent wasdistilled off under reduced pressure to obtain 260 mg of the targetsubstance as a brown solid.

¹H-NMR(CDCl₃) δ (ppm): 3.63 (1H, s), 3.64 (2H, brs), 5.12 (2H, brs),5.95 (1H, d, J=5.6 Hz), 6.69 (2H, dd, J=6.4 Hz, 2.0 Hz), 6.91 (2H, dd,J=6.4 Hz, 2.0 Hz), 7.81 (1H, d, J=5.6 Hz).

Production Example 186-3N-(4-{[2-Amino-3-(1-ethynyl)-4-pyridyl]oxy}phenyl)-N′-(4-fluorophenyl)urea

4-(4-Aminophenoxy)-3-(1-ethynyl)-2-pyridinamine (260 mg),para-fluorophenyl isocyanate (0.13 ml) and tetrahydrofuran (5 ml) werestirred at room temperature for 20 hours. Water was added to thereaction solution, the tetrahydrofuran was distilled off, and then asmall amount of ethyl acetate was added and the precipitated solid wasfiltered off to obtain 20 mg of a light brown solid.

¹H-NMR (DMSO-d₆) δ (ppm): 4.53 (1H, s), 5.80 (1H, d, J=5.6 Hz), 6.22(2H, brs), 7.00-7.15 (4H, m), 7.40-7.53 (4H, m), 7.76 (1H, d, J=5.6 Hz),8.69 (1H, s), 8.73 (1H, s).

Example 187N1-Cyclopropyl-5-[(2-{[4-(4-hydroxypiperidino)butanoyl]amino}-4-pyridyl)oxy]-1H-1-indolecarboxamide

Phenyl N-cyclopropylcarbamate (120 mg) was added to a solution of 260 mgof 5-[(2-{[4-(4-hydroxypiperidino)butanoyl]amino}-4-pyridyl)oxy]indole,53 mg of sodium hydride (60% in oil) and 5 ml of dimethylformamide whilestirring at room temperature. After stirring for 10 minutes, water wasadded and extraction was performed with ethyl acetate. NH type silicagel was added to the ethyl acetate layer, the solvent was distilled offunder reduced pressure and the reaction product was adsorbed onto thesilica gel. The silica gel was charged into a dry column packed with NHtype silica gel, and purification was performed by column chromatography(chloroform:methanol=30:1). The solvent was distilled off under reducedpressure, and the residue was dissolved in ethyl acetate and washedtwice with 1N aqueous sodium hydroxide. After drying over sodiumsulfate, the solvent was distilled off under reduced pressure to obtain20 mg of the target substance as a white powder.

¹H-NMR (DMSO-d₆) δ (ppm): 0.57-0.64 (2H, m), 0.68-0.75 (2H, m),1.24-1.34 (2H, m), 1.55-1.67 (4H, m), 1.83-1.94 (2H, m), 2.17 (2H, t,J=7.2 Hz), 2.28 (2H, t, J=7.2 Hz), 2.55-2.66 (2H, m), 2.73-2.80 (1H, m),3.30-3.40 (1H, m), 4.47 (1H, d, J=3.6 Hz), 6.62 (1H, dd, J=5.6 Hz, 2.4Hz), 6.64 (1H, d, J=3.6 Hz), 7.04 (1H, dd, J=8.8 Hz, 2.4 Hz), 7.36 (1H,d, J=2.4 Hz), 7.61 (1H, d, J=2.4 Hz), 7.87 (1H, d, J=3.6 Hz), 8.12 (1H,d, J=5.6 Hz), 8.25-8.30 (2H, m), 10.40 (1H, s).

Example 188N1-(2-Fluoroethyl)-5-[(2-{[4-(4-hydroxypiperidino)butanoyl]amino}-4-pyridyl)oxy]-1H-1-indolecarboxamide

The target substance was obtained using phenyl

N-(2-fluoroethyl)carbamate, in the same manner as Example 188.

¹H-NMR (DMSO-d₆) δ (ppm): 1.24-1.35 (2H, m), 1.57-1.67 (4H, m), 1.88(2H, t, J=10.4 Hz), 2.17 (2H, t, J=7.2 Hz), 2.28 (2H, t, J=7.2 Hz),2.56-2.55 (2H, m), 3.30-3.40 (1H, m), 3.55 (1H, q, J=4.8 Hz), 3.61 (1H,q, J=4.8 Hz), 4.48 (1H, d, J=4.0 Hz), 4.52 (1H, t, J=4.8 Hz), 4.64 (1H,t, J=4.8 Hz), 6.62 (1H, dd, J=5.6 Hz, 2.4 Hz), 6.70 (1H, d, J=3.6 Hz),7.05 (1H, dd, J=8.8 Hz, 2.4 Hz), 7.38 (1H, d, J=2.4 Hz), 7.62 (1H, d,J=2.4 Hz), 7.95 (1H, d, J=3.6 Hz), 8.12 (1H, d, J=5.6 Hz), 8.28 (1H, d,J=8.8 Hz), 8.44-8.49 (1H, m), 10.41 (1H, s).

Example 189N1-Phenyl-5-[(2-{[4-(4-hydroxypiperidino)butanoyl]amino}-4-pyridyl)oxy]-1H-1-indolecarboxamide

The target substance was obtained using phenyl isocyanate, in the samemanner as Example 187.

¹H-NMR (DMSO-d₆) δ (ppm): 1.24-1.35 (2H, m), 1.57-1.67 (4H, m),1.84-1.96 (2H, m), 2.18 (2H, t, J=6.8 Hz), 2.29 (2H, t, J=6.8 Hz),2.56-2.66 (2H, m), 3.30-3.40 (1H, m), 4.48 (1H, d, J=4.4 Hz), 6.65 (1H,dd, J=5.6 Hz, 2.4 Hz), 6.77 (1H, d, J=3.6 Hz), 7.09 (1H, dd, J=8.8 Hz,2.4 Hz), 7.10-7.16 (1H, m), 7.35-7.41 (2H, m), 7.43 (1H, d, J=2.4 Hz),7.62-7.67 (3H, m), 8.10-8.15 (2H, m), 8.27 (1H, d, J=8.8 Hz), 10.10 (1H,s), 10.42 (1H, s).

Example 190N1-Cyclopropyl-5-[(2-{[2-(4-hydroxypiperidino)acetyl]amino}-4-pyridyl)oxy]-1H-1-indolecarboxamide

The target substance was obtained using5-[(2-{[2-(4-hydroxypiperidino)acetyl]amino}-4-pyridyl)oxy]indole, inthe same manner as Example 188.

¹H-NMR (DMSO-d6) δ (ppm): 0.58-0.63 (2H, m), 0.69-0.75 (2H, m),1.35-1.45 (2H, m), 1.66-1.74 (2H, m), 2.17-2.25 (2H, m), 2.64-2.72 (2H,m), 2.72-2.80 (1H, m), 3.04 (2H, s), 3.38-3.49 (1H, m), 4.57 (1H, d,J=4.4 Hz), 6.65 (1H, d, J=3.6 Hz), 6.68 (1H, dd, J=5.6 Hz, 2.4 Hz), 7.05(1H, dd, J=8.8 Hz, 2.4 Hz), 7.38 (1H, d, J=2.8 Hz), 7.59 (1H, d, J=2.8Hz), 7.87 (1H, d, J=3.6 Hz), 8.15 (1H, d, J=5.6 Hz), 8.27-8.82 (2H, m),9.85 (1H, s).

The intermediate was obtained in the following manner.

Production Example 190-15-[(2-{[2-(4-Hydroxypiperidino)acetyl]amino}-4-pyridyl)oxy]indole

Bromoacetyl chloride (2.14 g) was added to a solution of 2.0 g ofN1-cyclopropyl-5-[(2-amino-4-pyridyl)oxy]-1H-1-indolecarboxamide, 2.3 mlof triethylamine and 20 ml of tetrahydrofuran while stirring at roomtemperature. After stirring for 30 minutes, water was added andextraction was performed with ethyl acetate. The extract was passedthrough a glass filter coated with silica gel. The silica gel wasthoroughly washed with ethyl acetate, and then the ethyl acetate layerswere combined and subjected to distillation under reduced pressure toobtain 900 mg of a greenish-brown oil. The 900 mg of oil was stirred at70° C. for 35 minutes together with 640 mg of 4-hydroxypiperidine, 1.2 gof potassium carbonate and 20 ml of dimethylformamide. Water was addedand extraction was performed with ethyl acetate. The extract was washed3 times with water and once with brine, and then passed through a glassfilter coated with silica gel. The silica gel was washed thoroughly withethyl acetate, and the solvent was distilled off under reduced pressureto obtain 530 mg of the target substance as a light yellow powder.

¹H-NMR (DMSO-d₆) δ (ppm): 1.35-1.47 (2H, m), 1.68-1.75 (2H, m), 2.21(2H, t, J=10.00 Hz), 2.64-2.74 (2H, m), 3.03 (2H, s), 3.40-3.50 (1H, m),4.57 (1H, d, J=4.0 Hz), 6.42 (1H, s), 6.63 (1H, dd, J=5.6 Hz, 2.4 Hz),6.86 (1H, dd, J=8.8 Hz, 2.4 Hz), 7.30 (1H, s), 7.42 (1H, d, J=2.4 Hz),7.45 (1H, d, J=8.8 Hz), 7.59 (1H, d, J=2.4 Hz), 8.12 (1H, d, J=5.6 Hz),9.81 (1H, s), 11.25 (1H, s).

Example 191N1-(2-Fluoroethyl)-5-[(2-{[2-(4-hydroxypiperidino)acetyl]amino}-4-pyridyl)oxy]-1H-1-indolecarboxamide

The target substance was obtained using5-[(2-{[2-(4-hydroxypiperidino)acetyl]amino}-4-pyridyl)oxy]indolephenyland N-(2-fluoroethyl)carbamate, in the same manner as Example 187.

¹H-NMR (DMSO-d₆) δ (ppm): 1.35-1.45 (2H, m), 1.66-1.74 (2H, m), 2.21(2H, t, J=10.0 Hz), 2.65-2.72 (2H, m), 3.04 (2H, s), 3.38-3.50 (1H, m),3.55 (1H, q, J=4.8 Hz), 3.62 (1H, q, J=4.8 Hz), 4.52 (1H, t, J=4.8 Hz),4.56 (1H, d, J=4.4 Hz), 4.64 (1H, t, J=4.8 Hz), 6.67 (1H, dd, J=5.6 Hz,2.4 Hz), 6.70 (1H, d, J=3.6 Hz), 7.06 (1H, dd, J=8.8 Hz, 2.4 Hz), 7.40(1H, d, J=2.4 Hz), 7.60 (1H, d, J=2.4 Hz), 7.95 (1H, d, J=3.6 Hz), 8.15(1H, d, J=5.6 Hz), 8.30 (1H, d, J=8.8 Hz), 8.47 (1H, t, J=4.8 Hz), 9.85(1H, s).

Example 192N1-Cyclopropyl-5-[(2-{[3-(4-hydroxypiperidino)propionyl]amino}-4-pyridyl)oxy]-1H-1-indolecarboxamide

The target substance was obtained using5-[(2-{[3-(4-hydroxypiperidino)propionyl]amino}-4-pyridyl)oxy]indole, inthe same manner as Example 187.

¹H-NMR (DMSO-d₆) δ (ppm): 0.58-0.64 (2H, m), 0.70-0.76 (2H, m),1.29-1.91 (2H, m), 1.62-1.72 (2H, m), 1.95-2.06 (2H, m), 2.38-2.58 (4H,m), 2.63-2.73 (2H, m), 2.70-2.80 (1H, m), 3.35-3.46 (1H, m), 4.51 (1H,s), 6.61-6.66 (2H, m), 7.04 (1H, dd, J=8.8 Hz, 2.4 Hz), 7.36 (1H, d,J=2.4 Hz), 7.59 (1H, d, J=2.4 HZ), 7.87 (1H, d, J=3.6 Hz), 8.13 (1H, d,J=5.6 Hz), 8.25-8.30 (2H, m), 10.77 (1H, s).

The intermediate was obtained in the following manner.

Production Example 192-15-[(2-{[3-(4-Hydroxypiperidino)propionyl]amino}-4-pyridyl)oxy]indole

3-Bromopropionyl chloride (1.4 ml) was added to a solution of 2.0 g ofN1-cyclopropyl-5-[(2-amino-4-pyridyl)oxy]-1H-1-indolecarboxamide, 2.3 mlof triethylamine and 80 ml of tetrahydrofuran, while stirring on ice.After stirring for 10 minutes, stirring was continued at roomtemperature for 10 minutes, water was added and extraction was performedwith ethyl acetate. The extract was passed through a glass filter coatedwith silica gel. The silica gel was thoroughly washed with ethylacetate, and then the ethyl acetate layers were combined and subjectedto distillation under reduced pressure to obtain 1.7 g of a faint yellowoil. A 900 mg portion of the oil was stirred at 70° C. for 30 minutestogether with 470 mg of 4-hydroxypiperidine, 880 mg of potassiumcarbonate and 10 ml of dimethylformamide. Water was added and extractionwas performed with ethyl acetate. NH type silica gel was added to theethyl acetate layer, the solvent was distilled off under reducedpressure and the reaction product was adsorbed onto the silica gel. Thesilica gel was charged into a dry column packed with NH type silica gel,and purification was performed by column chromatography(chloroform:methanol=100:3). The solvent was distilled off under reducedpressure to obtain 170 mg of the target substance as a white powder.

¹H-NMR (DMSO-d₆) δ (ppm): 1.29-1.42 (2H, m), 1.62-1.72 (2H, m), 2.00(2H, t, J=7.2 Hz), 2.37-2.55 (4H, m), 2.62-2.72 (2H, m), 3.35-3.46 (1H,m), 4.52 (1H, d, J=4.0 Hz), 6.42 (1H, s), 6.59 (1H, dd, J=5.6 Hz, 2.4Hz), 6.85 (1H, dd, J=8.8 Hz, 2.4 Hz), 7.29 (1H, s), 7.41 (1H, d, J=2.4Hz), 7.44 (1H, d, J=8.8 Hz), 7.59 (1H, d, J=2.4 Hz), 8.10 (1H, d, J=5.6Hz), 10.74 (1H, s), 11.22 (1H, s).

Example 193N1-(2-Fluoroethyl)-5-({2-[(4-piperidylcarbonyl)amino]-4-pyridyl}oxy)-1H-1-indolecarboxamide

After dissolving 160 mg ofN1-(2-fluoroethyl)-5-[(2-{[(1-tert-butyloxycarbonyl-4-piperidyl)carbonyl]amino}-4-pyridyl)oxy]-1H-1-indolecarboxamidein 10 ml of trifluoroacetic acid, the solution was stirred at roomtemperature for 10 minutes. Ethyl acetate and sodium bicarbonate waterwere added to alkalinity for liquid separation. The ethyl acetate layerwas washed once with brine and dried over magnesium sulfate. The solventwas distilled off under reduced pressure to obtain 86 mg of a colorlesspowder.

¹H-NMR (DMSO-d₆) δ (ppm): 1.60-1.73 (2H, m), 1.83-1.91 (2H, m),2.65-2.73 (1H, m), 2.77-2.87 (2H, m), 3.22-3.32 (2H, m), 3.55 (1H, q,J=5.2 Hz), 3.62 (1H, q, J=5.2 Hz), 4.52 (1H, t, J=5.2 Hz), 4.64 (1H, t,J=5.2 Hz), 6.67 (1H, dd, J=5.6 Hz, 2.4 Hz), 6.70 (1H, d, J=3.6 Hz), 7.05(1H, dd, J=8.8 Hz, 2.4 Hz), 7.38 (1H, d, J=2.4 Hz), 7.59 (1H, d, J=2.4Hz), 7.96 (1H, d, J=3.6 Hz), 8.16 (1H, d, J=5.6 Hz), 8.29 (1H, d, J=8.8Hz), 8.49 (1H, t, J=5.2 Hz), 10.59 (1H, s).

The intermediates were obtained in the following manner.

Production Example 193-1N1-(2-Fluoroethyl)-5-[(2-{[(1-tert-butyloxycarbonyl-4-piperidyl)carbonyl]amino}-4-pyridyl)oxy]-1H-1-indolecarboxamide

N1-(2-Fluoroethyl)-5-[(2-amino-4-pyridyl)oxy]-1H-1-indolecarboxamide(500 mg), 1-tert-butyloxycarbonylpiperidine-4-carboxylic acid (440 mg),benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(Bop Reagent) (840 mg), triethylamine (0.44 ml) and dimethylformamide(10 ml) were stirred at room temperature for 17 hours. Water was added,extraction was performed with ethyl acetate, NH type silica gel wasadded to the extract, the solvent was distilled off under reducedpressure and the reaction product was adsorbed onto the silica gel. Thesilica gel was charged into a dry column packed with NH type silica gel,and column purification was performed (hexane:ethyl acetate=1:1). Thesolvent was distilled off under reduced pressure to obtain 160 mg of thetarget substance as a white powder.

¹H-NMR (DMSO-d₆) δ (ppm): 1.28-1.40 (2H, m), 1.36 (9H, s), 1.64-1.72(2H, m), 2.54-2.80 (3H, m), 3.55 (1H, q, J=5.2 Hz), 3.61 (1H, q, J=5.2Hz), 3.86-3.96 (2H, m), 4.52 (1H, t, J=5.2 Hz), 4.64 (1H, t, J=5.2 Hz),6.66 (1H, dd, J=5.6 Hz, 2.4 Hz), 6.70 (1H, d, J=3.6 Hz), 7.05 (1H, dd,J=8.8 Hz, 2.4 Hz), 7.38 (1H, d, J=2.4 Hz), 7.59 (1H, d, J=2.4 Hz), 7.95(1H, d, J=3.6 Hz), 8.14 (1H, d, J=5.6 Hz), 8.28 (1H, d, J=8.8 Hz), 8.48(1H, t, J=5.2 Hz), 10.49 (1H, s).

Example 194N1-(2-Fluoroethyl)-5-[(2-{[(1-methyl-4-piperidyl)carbonyl]amino}-4-pyridyl)oxy]-1H-1-indolecarboxamide

N1-Cyclopropyl-5-({2-[(4-piperidylcarbonyl)amino]-4-pyridyl}oxy)-1H-1-indolecarboxamide(70 mg), formaldehyde (37% in water, 0.1 ml), acetic acid (20 mg) andtetrahydrofuran (5 ml) were stirred at room temperature for 5 minutes,and then 70 mg of sodium triacetoxyborohydride was added prior toadditional stirring for 10 minutes. Sodium bicarbonate water was addedand extraction was performed with ethyl acetate. The extract was passedthrough a glass filter coated with NH type silica gel. The silica gelwas thoroughly washed with ethyl acetate, and the ethyl acetate layerswere combined and subjected to distillation under reduced pressure toobtain 40 mg of a colorless powder.

¹H-NMR (DMSO-d₆) δ (ppm): 1.45-1.56 (2H, m), 1.59-1.68 (2H, m),1.73-1.83 (2H, m), 2.09 (3H, s), 2.30-2.40 (1H, m), 2.69-2.77 (2H, m),3.56 (1H, q, J=5.2 Hz), 3.62 (1H, q, J=5.2 Hz), 4.52 (1H, t, J=5.2 Hz),4.64 (1H, t, J=5.2 Hz), 6.65 (1H, dd, J=5.6 Hz, 2.4 Hz), 6.70 (1H, d,J=3.6 Hz), 7.05 (1H, dd, J=8.8 Hz, 2.4 Hz), 7.38 (1H, d, J=2.4 Hz), 7.60(1H, d, J=2.4 Hz), 7.95 (1H, d, J=3.6 Hz), 8.13 (1H, d, J=5.6 Hz), 8.29(1H, d, J=8.8 Hz), 8.48 (1H, t, J=5.2 Hz), 10.41 (1H, s).

Example 195N1-Cyclopropyl-5-({2-[(4-piperidylcarbonyl)amino]-4-pyridyl}oxy)-1H-1-indolecarboxamide

The target substance was obtained usingN1-cyclopropyl-5-[(2-{[(1-tert-butyloxycarbonyl-4-piperidyl)carbonyl]amino}-4-pyridyl)oxy]-1H-1-indolecarboxamide,in the same manner as Example 193.

¹H-NMR (DMSO-d₆) δ (ppm): 0.59-0.66 (2H, m), 0.67-0.75 (2H, m),1.30-1.43 (2H, m), 1.54-1.62 (2H, m), 2.36-2.45 (2H, m), 2.45-2.54 (1H,m), 2.73-2.80 (1H, m), 2.86-2.94 (2H, m), 6.60-6.67 (2H, m), 7.04 (1H,dd, J=8.8 Hz, 2.4 Hz), 7.36 (1H, d, J=2.4 Hz), 7.60 (1H, d, J=2.4 Hz),7.92 (1H, d, J=2.4 Hz), 8.13 (1H, d, J=5.6 Hz), 8.29 (1H, d, J=8.8 Hz),8.34 (1H, s), 10.36 (1H, s).

The intermediates were obtained in the following manner.

Production Example 195-1N1-Cyclopropyl-5-[(2-{[(1-tert-butyloxycarbonyl-4-piperidyl)carbonyl]amino}-4-pyridyl)oxy]-1H-1-indolecarboxamide

The target substance was obtained usingN1-cyclopropyl-5-[(2-amino-4-pyridyl)oxy]-1H-1-indolecarboxamide, in thesame manner as Production Example 193-1.

¹H-NMR (DMSO-d₆) δ (ppm): 0.59-0.64 (2H, m), 0.70-0.75 (2H, m),1.28-1.42 (11H, m), 1.64-1.71 (2H, m), 2.55-2.82 (4H, m), 3.87-3.97 (2H,m), 6.64-6.68 (2H, m), 7.03 (1H, dd, J=8.8 Hz, 2.4 Hz), 7.36 (1H, d,J=2.4 Hz), 7.59 (1H, d, J=2.4 Hz), 7.87 (1H, d, J=3.6 Hz), 8.14 (1H, d,J=5.6 Hz), 8.27 (1H, s), 8.29 (1H, d, J=8.8 Hz), 10.48 (1H, s).

Example 196N1-Cyclopropyl-5-[(2-{[(1-methyl-4-piperidyl)carbonyl]amino}-4-pyridyl)oxy]-1H-1-indolecarboxamide

The target substance was obtained usingN1-cyclopropyl-5-({2-[(4-piperidylcarbonyl)amino]-4-pyridyl}oxy)-1H-1-indolecarboxamide,in the same manner as Example 194.

¹H-NMR (DMSO-d₆) δ (ppm): 0.59-0.65 (2H, m), 0.70-0.76 (2H, m),1.43-1.56 (2H, m), 1.59-1.68 (2H, m), 1.70-1.81 (2H, m), 2.09 (3H, s),2.30-2.40 (1H, m), 2.69-2.80 (3H, m), 6.62-6.70 (2H, m), 7.04 (1H, dd,J=8.8 Hz, 2.4 Hz), 7.36 (1H, d, J=2.4 Hz), 7.59 (1H, d, J=2.4 Hz), 7.87(1H, d, J=3.6 Hz), 8.13 (1H, d, J=5.6 Hz), 8.27-8.83 (2H, m), 10.41 (1H,s).

Example 197N1-Phenyl-5-[(2-{[(1-methyl-4-piperidyl)carbonyl]amino}-4-pyridyl)oxy]-1H-1-indolecarboxamide

The target substance was obtained using

N1-phenyl-5-({2-[(4-piperidylcarbonyl)amino]-4-pyridyl}oxy)-1H-1-indolecarboxamide,in the same manner Example 194.

¹H-NMR (DMSO-d₆) δ (ppm): 1.44-1.56 (2H, m), 1.59-1.67 (2H, m),1.73-1.82 (2H, m), 2.09 (3H, s), 2.30-2.44 (1H, s), 2.69-2.76 (2H, s),6.66-6.70 (1H, m), 6.77 (1H, d, J=3.6 Hz), 7.07-7.15 (2H, m), 7.35-7.45(3H, m), 7.60-7.68 (3H, m), 8.10-8.18 (2H, m), 8.27 (1H, d, J=8.8 Hz),10.10 (1H, s), 10.42 (1H, s).

The intermediates were obtained in the following manner.

Production Example 197-1N1-Phenyl-5-[(2-amino-4-pyridyl)oxy]-1H-1-indolecarboxamide

After adding 28 mg of sodium hydride (60% in oil) to a solution of 3.0 gof 5-[(2-amino-4-pyridyl)oxy]-1H-indole in dimethylformamide at roomtemperature and stirring the mixture for 5 minutes, 1.6 g of phenylisocyanate was added and the mixture was stirred for 20 minutes. Waterwas added, extraction was performed with ethyl acetate and the organiclayer was washed with water, and then silica gel was added and thesolvent was distilled off under reduced pressure. The silica gel wascharged into a dry column packed with silica gel and purified by columnchromatography (ethyl acetate), to obtain 3.4 g of a colorless powder.

¹H-NMR (DMSO-d₆) δ (ppm): 5.77 (1H, d, J=2.4 Hz), 5.85 (2H, s), 6.14(1H, dd, J=5.6 Hz, 2.4 Hz), 6.75 (1H, d, J=4.0 Hz), 7.06 (1H, dd, J=8.8Hz, 2.4 Hz), 7.13 (1H, dd, J=8.0 Hz, 8.0 Hz), 7.36-7.43 (3H, m), 7.64(2H, d, J=8.0 Hz), 7.77 (1H, d, J=5.6 Hz), 8.10 (1H, d, J=4.0 Hz), 8.25(1H, d, J=8.8 Hz), 10.08 (1H, s).

Production Example 197-2 Tert-butyl4-{[(4-{[1-(anilinocarbonyl)-1H-5-indolyl]oxy}-2-pyridyl)amino]carbonyl}-1-piperidinecarboxylate

The target substance was obtained usingN1-phenyl-5-[(2-amino-4-pyridyl)oxy]-1H-1-indolecarboxamide, in the samemanner as Production Example 193-1.

¹H-NMR (DMSO-d₆) δ (ppm): 1.38-1.41 (11H, m), 1.64-1.72 (2H, m),2.52-2.75 (3H, m), 3.87-3.97 (2H, m), 6.68 (1H, dd, J=5.6 Hz, 2.4 Hz),6.77 (1H, d, J=3.6 Hz), 7.09 (1H, dd, J=8.8 Hz, 2.4 Hz), 7.13 (1H, dd,J=7.2 Hz, 7.2 Hz), 7.38 (2H, dd, J=7.2 Hz, 7.2 Hz), 7.43 (1H, d, J=2.4Hz), 7.61 (1H, d, J=2.4 Hz), 7.65 (2H, d, J=7.2 Hz), 8.13 (1H, d, J=3.6Hz), 8.15 (1H, d, J=5.6 Hz), 8.27 (1H, d, J=8.8 Hz), 10.10 (1H, s),10.50 (1H, s).

Production Example 197-3N1-Phenyl-5-({2-[(4-piperidylcarbonyl)amino]-4-pyridyl}oxy)-1H-1-indolecarboxamide

The target substance was obtained using tert-butyl4-{[(4-{[1-(anilinocarbonyl)-1H-5-indolyl]oxy}-2-pyridyl)amino]carbonyl}-1-piperidinecarboxylate, in the same manner as Example 193.

¹H-NMR (DMSO-d₆) δ (ppm): 1.32-1.43 (2H, m), 1.55-1.63 (2H, m),2.37-2.53 (3H, m), 2.88-2.95 (2H, m), 6.67 (1H, dd, J=5.6 Hz, 2.4 Hz),6.77 (1H, d, J=3.6 Hz), 7.09 (1H, dd, J=8.8 Hz, 2.4 Hz), 7.13 (1H, dd,J=7.2 Hz, 7.2 Hz), 7.38 (2H, dd, J=7.2 Hz, 7.2 Hz), 7.43 (1H, 2.4 Hz),7.62-7.67 (3H, m), 8.13 (1H, d, J=3.6 Hz), 8.15 (1H, d, J=5.6 Hz), 8.27(1H, d, J=8.8 Hz), 10.10 (1H, bs), 10.40 (1H, s).

Example 198N1-Phenyl-5-{[2-({[(1-cyclopropylmethyl)-4-piperidyl]carbonyl}amino)-4-pyridyl]oxy}-1H-1-indolecarboxamide

The target substance was obtained usingN1-phenyl-5-({2-[(4-piperidylcarbonyl)amino]-4-pyridyl}oxy)-1H-1-indolecarboxamideand cyclopropanecarboxyaldehyde, in the same manner as Example 194.

¹H-NMR (DMSO-d₆) δ (ppm): 0.00-0.06 (2H, m), 0.39-0.45 (2H, m),0.72-0.82 (1H, m), 1.46-1.59 (2H, m), 1.60-1.70 (2H, m), 1.80-1.90 (2H,m), 2.10 (2H, d, J=6.0 Hz), 2.33-2.43 (1H, m), 2.90-3.00 (2H, m), 6.67(1H, dd, J=5.6 Hz, 2.4 Hz), 6.76 (1H, d, J=3.6 Hz), 7.06-7.16 (2H, m),7.35-7.45 (3H, m), 7.60-7.68 (3H, m), 8.12 (1H, d, J=3.6 Hz), 8.14 (1H,d, J=5.6 Hz), 8.27 (1H, d, J=8.8 Hz), 10.09 (1H, s), 10.40 (1H, s).

Example 199N4-(4-{4-[(Anilinocarbonyl)amino]-3-chlorophenoxy}-2-pyridyl)-1-methyl-4-piperidinecarboxamide

After dissolving 120 mg of t-butyl4-{[(4-{4-[(anilinocarbonyl)amino]-3-chlorophenoxy}-2-pyridyl)amino]carbonyl}-1-piperidinecarboxylate in 5 ml of trifluoroacetic acid, the solution was stirred atroom temperature for 5 minutes. Sodium bicarbonate water and 5N aqueoussodium hydroxide were added and extraction was performed with ethylacetate. The extract was washed with brine and dried over sodiumsulfate. The drying agent was filtered off, and the solvent wasdistilled off under reduced pressure. After adding 5 ml oftetrahydrofuran, 26 mg of acetic acid, 92 mg of sodiumtriacetoxyborohydride and 0.5 ml of formaldehyde (37% in water) to theresidue, the mixture was stirred at room temperature for 10 minutes.Sodium bicarbonate water and 5N aqueous sodium hydroxide were added tothe reaction solution, and extraction was performed with ethyl acetate.The extract was washed with brine and then passed through a glass filtercoated with NH type silica gel. The silica gel was washed thoroughlywith ethyl acetate, the ethyl acetate layers were combined and subjectedto distillation under reduced pressure, and the residue was solidifiedwith ethyl acetate and hexane to obtain 80 mg of a colorless powder.

¹H-NMR (DMSO-d₆) δ (ppm): 1.48-1.62 (2H, m), 1.62-1.72 (2H, m),1.76-1.86 (2H, m), 2.12 (3H, s), 2.34-2.44 (1H, m), 2.72-2.81 (2H, m),6.68 (1H, dd, J=5.6 Hz, 2.4 Hz), 6.98 (1H, dd, J=7.2 Hz, 7.2 Hz), 7.15(1H, dd, J=8.8 Hz, 2.4 Hz), 7.29 (2H, dd, J=7.2 Hz, 7.2 Hz), 7.38 (1H,d, J=2.4 Hz), 7.46 (2H, d, J=7.2 Hz), 7.66 (1H, d, J=2.4 Hz), 8.17 (1H,d, J=5.6 Hz), 8.22 (1H, d, J=8.8 Hz), 8.38 (1H, s), 9.42 (1H, s), 10.49(1H, s).

Production Example 199-1 t-Butyl4-({[4-(4-amino-3-chlorophenoxy)-2-pyridyl]amino}carbonyl)-1-piperidinecarboxylate

2-Amino-4-(4-amino-3-chlorophenoxy)pyridine (600 mg),1-t-butyloxycarbonylpiperidine-4-carboxylic acid (700 mg),benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(Bop Reagent) (1.4 g), triethylamine (0.71 ml) and dimethylformamide (10ml) were stirred at 60° C. for 3.5 hours and then at room temperaturefor 19 hours. Water was added to the reaction solution, extraction wasperformed with ethyl acetate and the organic layer was washed withwater, after which silica gel was added and the solvent was distilledoff under reduced pressure. The silica gel was charged into a dry columnpacked with silica gel, and purification was performed by columnchromatography (hexane:ethyl acetate=1:1, followed by ethyl acetate) toobtain 660 mg of a reddish-brown powder.

¹H-NMR (DMSO-d₆) δ (ppm): 1.30-1.45 (11H, m), 1.65-1.74 (2H, m),2.56-2.76 (3H, m), 3.88-4.03 (2H, m), 5.37 (2H, s), 6.59 (1H, dd, J=5.6Hz, 2.4 Hz), 6.82-6.88 (2H, m), 6.07 (1H, d, J=2.4 Hz), 7.57 (1H, d,J=2.4 Hz), 8.12 (1H, d, J=5.6 Hz), 10.48 (1H, s).

Production Example 199-2 t-Butyl4-{[(4-{3-chloro-4-[(phenoxycarbonyl)amino]phenoxy}-2-pyridyl)amino]carbonyl}-1-piperidinecarboxylate

After adding 0.21 ml of phenyl chloroformate to a solution of 660 mg oft-butyl4-({[4-(4-amino-3-chlorophenoxy)-2-pyridyl]amino}carbonyl)-1-piperidinecarboxylate, 0.14 ml of pyridine and 10 ml of tetrahydrofuran whilestirring at room temperature, the mixture was further stirred for 13hours. Water was added to the reaction solution, extraction wasperformed with ethyl acetate and the organic layer was washed withwater, after which silica gel was added and the solvent was distilledoff under reduced pressure. The silica gel was charged into a dry columnpacked with silica gel, and purification was performed by columnchromatography (hexane:ethyl acetate=1:1, followed by ethyl acetate) toobtain 500 mg of a colorless oil.

¹H-NMR (DMSO-d₆) δ (ppm): 1.30-1.45 (11H, m), 1.67-1.77 (2H, m),2.58-2.80 (3H, m), 3.88-4.00 (2H, m), 6.71 (1H, dd, J=5.6 Hz, 2.4 Hz),7.17-7.28 (4H, m), 7.37-7.46 (3H, m), 7.67 (1H, d, J=2.4 Hz), 7.79 (1H,d, J=8.8 Hz), 8.20 (1H, d, J=5.6 Hz), 9.78 (1H, bs), 10.58 (1H, s).

Production Example 199-3 t-Butyl4-{[(4-{4-[(anilinocarbonyl)amino]-3-chlorophenoxy}-2-pyridyl)amino]carbonyl}-1-piperidinecarboxylate

t-Butyl4-{[(4-{3-chloro-4-[(phenoxycarbonyl)amino]phenoxy}-2-pyridyl)amino]carbonyl}-1-piperidinecarboxylate (250 mg), aniline (84 mg) and dimethylformamide (3 ml) werestirred at 130° C. for 70 minutes. The mixture was returned to roomtemperature, water was added and extraction was performed with ethylacetate. Silica gel was added to the extract, the solvent was distilledoff under reduced pressure, and the reaction product was adsorbed ontothe silica gel. The silica gel was charged into a dry column packed withsilica gel, and column purification was performed (hexane:ethylacetate=1:1, followed by ethyl acetate). The solvent was distilled offunder reduced pressure to obtain 120 mg of a colorless oil.

¹H-NMR (DMSO-d₆) δ (ppm): 1.28-1.45 (11H, m), 1.67-1.75 (2H, m),2.57-2.80 (3H, m), 3.87-4.03 (2H, m), 6.69 (1H, dd, J=5.6 Hz, 2.4 Hz),6.93 (1H, dd, J=7.2 Hz, 7.2 Hz), 7.15 (1H, dd, J=8.8 Hz, 2.4 Hz), 7.28(2H, dd, J=7.2 Hz, 7.2 Hz), 7.39 (1H, d, J=2.4 Hz), 7.45 (2H, d, J=7.2Hz), 7.64 (1H, d, J=2.4 Hz), 8.18 (1H, d, J=5.6 Hz), 8.21 (1H, d, J=8.8Hz), 8.36 (1H, s), 9.33 (1H, s), 10.55 (1H, s).

Example 200N4-[4-(3-Chloro-4-{[(cyclopropylamino)carbonyl]amino}phenoxy)-2-pyridyl]-1-methyl-4-piperidinecarboxamide

The target substance was obtained using t-butyl4-({[4-(3-chloro-4-{[(cyclopropylamino)carbonyl]amino}phenoxy)-2-pyridyl]amino}carbonyl)-1-piperidinecarboxylate, in the same manner as Example 199.

¹H-NMR (DMSO-d₆) δ (ppm): 0.38-0.48 (2H, brs), 0.60-0.70 (2H, m),1.50-1.85 (6H, m), 2.11 (3H, s), 2.33-2.45 (1H, m), 2.45-2.58 (1H, m),2.70-2.80 (2H, m), 6.66 (1H, dd, J=5.6 Hz, 2.4 Hz), 7.09 (1H, dd, J=8.8Hz, 2.4 Hz), 7.16 (1H, d, J=2.4 Hz), 7.32 (1H, d, J=2.4 Hz), 7.62 (1H,s), 7.93 (1H, s), 8.16 (1H, d, J=5.6 Hz), 8.20 (1H, d, J=8.8 Hz), 10.46(1H, s).

The intermediates were obtained in the following manner.

Production Example 200-1 t-Butyl4-({[4-(3-chloro-4-{[(cyclopropylamino)carbonyl]amino}phenoxy)-2-pyridyl]amino}carbonyl)-1-piperidinecarboxylate

The target substance was obtained using cyclopropylamine with thestarting material synthesized in Production Example 199-2, in the samemanner as Production Example 199-3.

¹H-NMR (DMSO-d₆) δ (ppm): 0.38-0.44 (2H, m), 0.60-0.68 (2H, m),1.30-1.44 (11H, m), 1.67-1.74 (2H, m), 2.50-2.80 (4H, m), 3.88-4.00 (2H,m), 6.67 (1H, dd, J=5.6 Hz, 2.4 Hz), 7.09 (1H, dd, J=8.8 Hz, 2.4 Hz),7.16 (1H, d, J=2.4 Hz), 7.32 (1H, d, J=2.4 Hz), 7.61 (1H, s), 7.93 (1H,s), 8.16 (1H, d, J=5.6 Hz), 8.20 (1H, d, J=8.8 Hz), 10.54 (1H, s).

Example 201N4-[4-(3-Chloro-4-{[(4-fluoroanilino)carbonyl]amino}phenoxy)-2-pyridyl]-4-piperidinecarboxamide

After dissolving 320 mg of t-butyl4-{[4-(3-chloro-4-{[(4-fluoroanilino)carbonyl]amino}phenoxy)-2-pyridyl]amino}carbonyl)-1-piperidinecarboxylatein 10 ml of trifluoroacetic acid, the solution was stirred at roomtemperature for 5 minutes. Ethyl acetate and sodium bicarbonate waterwere added to alkalinity for liquid separation. The ethyl acetate layerwas washed once with brine and then dried over magnesium sulfate. Thesolvent was distilled off under reduced pressure to obtain 240 mg of acolorless powder.

¹H-NMR (DMSO-d₆) δ (ppm): 1.36-1.48 (2H, m), 1.58-1.66 (2H, m),2.39-2.58 (3H, m), 2.89-2.98 (2H, m), 6.67 (1H, dd, J=5.6 Hz, 2.4 Hz),7.09-7.18 (3H, m), 7.38 (1H, d, J=2.4 Hz), 7.44-7.50 (2H, m), 7.66 (1H,d, J=2.4 Hz), 8.15 (2H, m), 8.38 (1H, s), 9.48 (1H, s), 10.44 (1H, s).

The intermediates were obtained in the following manner.

Production Example 201-1 t-Butyl4-{[4-(3-chloro-4-{[(4-fluoroanilino)carbonyl]amino}phenoxy)-2-pyridyl]amino}carbonyl-1-piperidinecarboxylate

The target substance was obtained using para-fluoroaniline with thestarting material synthesized in Production Example 199-2, in the samemanner as Production Example 199-3.

¹H-NMR (DMSO-d₆) δ (ppm): 1.32-1.46 (11H, m), 1.66-1.75 (2H, m),2.56-2.78 (3H, m), 3.88-4.00 (2H, m), 6.69 (1H, dd, J=5.6 Hz, 2.4 Hz),7.10-7.18 (3H, m), 7.38 (1H, d, J=2.4 Hz), 7.43-7.50 (2H, m), 7.64 (1H,d, J=2.4 Hz), 8.17-8.23 (2H, m), 8.37 (1H, s), 9.45 (1H, s), 10.55 (1H,s).

Example 202N4-[4-(3-Chloro-4-{[(4-fluoroanilino)carbonyl]amino}phenoxy)-2-pyridyl]-1-methyl-4-piperidinecarboxamide

The target substance was obtained usingN4-[4-(3-chloro-4-{[(4-fluoroanilino)carbonyl]amino}phenoxy)-2-pyridyl]-4-piperidinecarboxamide,in the same manner as Example 199.

¹H-NMR (DMSO-d₆) δ (ppm): 1.48-1.60 (2H, m), 1.62-1.70 (2H, m),1.74-1.83 (2H, m), 2.11 (3H, s), 2.33-2.43 (1H, m), 2.70-2.78 (2H, m),6.68 (1H, dd, J=5.6 Hz, 2.4 Hz), 7.10-7.20 (3H, m), 7.39 (1H, d, J=2.4Hz), 7.44-7.50 (2H, m), 7.65 (1H, d, J=2.4 Hz), 8.16-8.23 (2H, m), 8.33(1H, s), 9.41 (1H, s), 10.47 (1H, s).

Example 203N1-(4-{4-[(Anilinocarbonyl)amino]-3-chlorophenoxy}-2-pyridyl)-2-(1-methyl-4-piperidyl)acetamide

The target substance was obtained using tert-butyl4-{2-[(4-{4-[(anilinocarbonyl)amino]-3-chlorophenoxy}-2-pyridyl)amino]-2-oxoethyl}-1-piperidinecarboxylate, in the same manner as Example 199.

¹H-NMR (DMSO-d₆) δ (ppm): 1.10-1.20 (2H, m), 1.50-1.70 (3H, m),1.72-1.80 (2H, m), 2.08 (3H, s), 2.24 (2H, d, J=6.8 Hz), 2.63-2.72 (2H,m), 6.66 (1H, d, J=5.6 Hz, 2.4 Hz), 6.97 (1H, dd, J=7.2 Hz, 7.2 Hz),7.14 (1H, dd, J=8.8 Hz, 2.4 Hz), 7.28 (2H, dd, J=7.2 Hz, 7.2 Hz), 7.39(1H, d, J=2.4 Hz), 7.47 (2H, d, J=7.2 Hz), 7.68 (1H, d, J=2.4 Hz), 8.16(1H, d, J=5.6 Hz), 8.20 (1H, d, J=8.8 Hz), 8.40 (1H, s), 9.42 (1H, s),10.48 (1H, s).

The intermediates were obtained in the following manner.

Production Example 203-1 tert-Butyl4-(2-{[4-(4-amino-3-chlorophenoxy)-2-pyridyl]amino}-2-oxoethyl)-1-piperidinecarboxylate

2-Amino-4-(4-amino-3-chlorophenoxy)pyridine (1.0 g), Bop reagent (1.9g), triethylamine (1.2 ml),2-[1-(tert-butoxycarbonyl)-4-piperidyl]acetic acid (1.0 g) anddimethylformamide (10 ml) were stirred at 60° C. for 2 hours and then atroom temperature for 18 hours. Water was added to the reaction solution,and extraction was performed with ethyl acetate. Silica gel was added tothe extract solution and the solvent was distilled off under reducedpressure. The silica gel was charged into a dry column packed withsilica gel, and purification was performed by column chromatography(hexane:ethyl acetate=1:1) to obtain 570 mg of a light brown oil.

¹H-NMR (DMSO-d₆) δ (ppm): 0.95-1.07 (2H, m), 1.36 (9H, s), 1.53-1.62(2H, m), 1.30-1.43 (1H, m), 2.25 (2H, d, J=7.2 Hz), 2.55-2.75 (2H, m),3.80-3.92 (2H, m), 5.37 (2H, s), 6.58 (1H, dd, J=5.6 Hz, 2.4 Hz),6.80-6.90 (2H, m), 7.07 (1H, d, J=2.4 Hz), 7.61 (1H, d, J=2.4 Hz), 8.11(1H, d, J=5.6 Hz), 10.43 (1H, s).

Production Example 203-2 tert-Butyl4-{2-[(4-{4-[(anilinocarbonyl)amino]-3-chlorophenoxy}-2-pyridyl)amino]-2-oxoethyl}-1-piperidinecarboxylate

Phenyl chloroformate (210 mg) was added dropwise to a solution of 570 mgof tert-butyl4-(2-{[4-(4-amino-3-chlorophenoxy)-2-pyridyl]amino}-2-oxoethyl)-1-piperidinecarboxylate,110 mg of pyridine and 5 ml of dimethylformamide while stirring at roomtemperature, and the mixture was further stirred for 30 minutes. Waterwas added and extraction was performed with ethyl acetate. The organiclayer was washed twice with water and once with brine, and then silicagel was added and the solvent was distilled off under reduced pressure.This was then charged into a dry column packed with silica gel andpurification was performed by column chromatography (hexane:ethylacetate=1:1, followed by ethyl acetate), to obtain 440 mg of tert-butyl4-{2-[(4-{3-chloro-4-[(phenoxycarbonyl)amino]phenoxy}-2-pyridyl)amino]-2-oxoethyl}-1-piperidinecarboxylateas a light yellow oil. After adding 71 mg of aniline and 5 ml ofdimethylformamide to the oil, it was stirred at 130° C. for 15 minutes.The reaction solution was returned to room temperature, NH type silicagel was added, the solvent was distilled off under reduced pressure andthe reaction product was adsorbed onto the silica gel. The silica gelwas charged into a dry column packed with NH type silica gel, and columnpurification was performed (hexane:ethyl acetate=1:1). The solvent wasdistilled off under reduced pressure to obtain 180 mg of the targetsubstance.

¹H-NMR (DMSO-d₆) δ (ppm): 0.94-1.06 (2H, m), 1.36 (9H, s), 1.53-1.61(2H, m), 1.80-1.92 (1H, m), 2.27 (2H, d, J=6.8 Hz), 2.55-2.75 (2H, m),3.80-3.90 (2H, m), 6.67 (1H, dd, J=5.6 Hz, 2.4 Hz), 6.98 (1H, dd, J=7.2Hz, 7.2 Hz), 7.15 (1H, dd, J=8.8 Hz, 2.4 Hz), 7.28 (2H, dd, J=7.2 Hz,7.2 Hz), 7.39 (1H, d, J=2.4 Hz), 7.45 (2H, d, J=7.2 Hz), 7.67 (1H, s),8.17 (1H, d, J=5.6 Hz), 8.21 (1H, d, J=8.8 Hz), 8.36 (1H, s), 9.38 (1H,s), 10.50 (1H, s).

Example 204N1-Phenyl-5-[(2-{[2-(1-methyl-4-piperidyl)acetyl]amino}-4-pyridyl)oxy]-1H-1-indolecarboxamide

The target substance was obtained using tert-butyl4-{2-[(4-{[1-(anilinocarbonyl)-1H-5-indolyl]oxy}-2-pyridyl)amino]-2-oxoethyl}-1-piperidinecarboxylate,in the same manner as Example 199.

¹H-NMR (DMSO-d₆) δ (ppm): 1.08-1.20 (2H, m), 1.48-1.66 (3H, m),1.71-1.80 (2H, m), 2.07 (3H, s), 2.22 (2H, d, J=7.2 Hz), 2.62-2.69 (2H,m), 6.65 (1H, dd, J=5.6 Hz, 2.4 Hz), 6.77 (1H, d, J=3.6 Hz), 7.07-7.16(2H, m), 7.38 (2H, dd, J=7.2 Hz, 7.2 Hz), 7.43 (1H, d, J=2.4 Hz),7.60-7.68 (3H, m), 8.10-8.17 (2H, m), 8.27 (1H, d, J=8.8 Hz), 10.09 (1H,s), 10.43 (1H, s).

The intermediates were obtained in the following manner.

Production Example 204-1 tert-Butyl4-{2-[(4-{[1-(anilinocarbonyl)-1H-5-indolyl]oxy}-2-pyridyl)amino]-2-oxyethyl}-1-piperidinecarboxylate

N1-Phenyl-5-[(2-amino-4-pyridyl)oxy]-1H-1-indolecarboxamide (500 mg),2-[1-(tert-butoxycarbonyl)-4-piperidyl]acetic acid (350 mg),benzotriazol-1-yltris(dimethylamino)phosphonium hexafluorophosphate (640mg), triethylamine (0.4 ml) and dimethylformamide (5 ml) were stirred at60° C. for 1 hour and then at room temperature for 19 hours. Water wasadded to the reaction solution and extraction was performed with ethylacetate. The organic layer was washed twice with water and once withbrine, and then silica gel was added and the solvent was distilled offunder reduced pressure. The silica gel was then charged into a drycolumn packed with silica gel and purification was performed by columnchromatography (hexane:ethyl acetate=1:1, followed by ethyl acetate), toobtain 220 mg of a colorless oil.

¹H-NMR (DMSO-d₆) δ (ppm): 0.92-1.08 (2H, m), 1.36 (9H, s), 1.50-1.62(2H, m), 1.77-1.90 (1H, m), 2.24 (2H, d, J=6.8 Hz), 2.55-2.77 (2H, m),3.78-3.93 (2H, m), 6.66 (1H, dd, J=5.6 Hz, 2.4 Hz), 6.77 (1H, d, J=3.6Hz), 7.08-7.16 (2H, m), 7.35-7.46 (3H, m), 7.60-7.68 (3H, m), 8.10-8.18(2H, m), 8.27 (1H, d, J=8.8 Hz), 10.09 (1H, s), 10.44 (1H, s).

Example 205N1-Phenyl-3-chloro-5-[(2-{[(1-methyl-4-piperidyl)carbonyl]amino}-4-pyridyl)oxy]-1H-1-indolecarboxamide

After dissolving 260 mg of tert-butyl4-{[(4-{[1-(anilinocarbonyl)-3-chloro-1H-5-indolyl]oxy}-2-pyridyl)amino]carbonyl}-1-piperidinecarboxylatein 5 ml of trifluoroacetic acid, the solution was stirred at roomtemperature for 5 minutes. Sodium bicarbonate water and 5N aqueoussodium hydroxide were added, and the mixture was extracted with ethylacetate and dried over magnesium sulfate. The drying agent was filteredoff and the solvent was distilled off under reduced pressure to obtain200 mg ofN1-phenyl-3-chloro-5-[(2-{[(4-piperidyl)carbonyl]amino}-4-pyridyl)oxy]-1H-1-indolecarboxamideas a faint yellow solid. After adding 0.5 ml of formaldehyde (37% inwater), 170 mg of sodium triacetoxyborohydride, 50 mg of acetic acid and5 ml of tetrahydrofuran to the solid, the mixture was stirred at roomtemperature for 10 minutes. Sodium bicarbonate water and 5N aqueoussodium hydroxide were added, extraction was performed with ethylacetate, and the extract was washed once with brine. The obtained ethylacetate solution was passed through a glass filter coated with NH typesilica gel. The silica gel was washed with ethyl acetate, and thesolvent was distilled off under reduced pressure to obtain 210 mg of afaint yellow oil. The oil was solidified from a hexane and ethyl acetatemixed solvent to obtain 90 mg of a powder.

¹H-NMR (DMSO-d₆) δ (ppm): 1.44-1.56 (2H, m), 1.60-1.68 (2H, m),1.73-1.82 (2H, m), 2.09 (3H, s), 2.30-2.45 (1H, m), 2.70-2.76 (2H, m),6.69 (1H, dd, J=5.6 Hz, 2.4 Hz), 7.14 (1H, dd, J=7.2 Hz, 7.2 Hz), 7.22(1H, dd, J=8.8 Hz, 2.4 Hz), 7.34-7.42 (3H, m), 7.60-7.66 (3H, m), 8.17(1H, d, J=5.6 Hz), 8.33 (1H, d, J=8.8 Hz), 8.38 (1H, s), 10.12 (1H, s),10.45 (1H, s).

The intermediates were obtained in the following manner.

Production Example 205-1 5-[(2-Amino-4-pyridyl)oxy]-3-chloro-1H-1-indole

5-[(2-Amino-4-pyridyl)oxy]-1H-1-indole (1.0 g), N-chlorosuccinimide (650mg) and isopropanol (20 ml) were stirred at 80° C. for 25 minutes. Waterwas added to the reaction solution and extraction was performed withethyl acetate. The extract was passed through a glass filter coated withNH type silica gel. The silica gel was washed with ethyl acetate, andthe solvent was distilled off under reduced pressure to obtain 1.3 g ofa reddish-brown oil.

¹H-NMR (DMSO-d₆) δ (ppm): 5.73 (1H, d, J=2.4 Hz), 5.82 (2H, s), 6.13(1H, dd, J=5.6 Hz, 2.4 Hz), 6.93 (1H, dd, J=8.8 Hz, 2.4 Hz), 7.15 (1H,d, J=2.4 Hz), 7.48 (1H, d, J=8.8 Hz), 7.58 (1H, d, J=2.4 Hz), 7.75 (1H,d, J=5.6 Hz), 11.48 (1H, s).

Production Example 205-2N1-Phenyl-5-[(2-amino-4-pyridyl)oxy]-3-chloro-1H-1-indolecarboxamide

Phenyl isocyanate was added dropwise to a solution of 1.3 g of5-[(2-amino-4-pyridyl)oxy]-3-chloro-1H-1-indole, 180 mg of sodiumhydride and 15 ml of dimethylformamide, and the mixture was stirred for20 minutes. Water was added to the reaction solution and extraction wasperformed with ethyl acetate. Silica gel was added to the extract andthe solvent was distilled off under reduced pressure. The silica gel wascharged into a dry column packed with silica gel and purification wasperformed by column chromatography (hexane:ethyl acetate=1:1, followedby ethyl acetate), to obtain 380 mg of a light red oil.

¹H-NMR (DMSO-d₆) δ (ppm): 5.79 (1H, d, J=2.4 Hz), 5.89 (2H, s), 6.16(1H, dd, J=5.6 Hz, 2.4 Hz), 7.12-7.20 (2H, m), 7.28 (1H, d, J=2.4 Hz),7.35-7.42 (2H, m), 7.64 (2H, d, J=8.0 Hz), 7.79 (1H, d, J=5.6 Hz), 8.31(1H, d, J=8.8 Hz), 8.35 (1H, s), 10.09 (1H, s).

Production Example 205-3 tert-Butyl4-{[(4-{[1-(anilinocarbonyl)-3-chloro-1H-5-indolyl]oxy}-2-pyridyl)amino]carbonyl}-1-piperidinecarboxylate

The target substance was obtained usingN1-phenyl-5-[(2-amino-4-pyridyl)oxy]-3-chloro-1H-1-indolecarboxamide, inthe same manner as Production Example 204-1.

¹H-NMR (DMSO-d₆) δ (ppm): 1.30-1.43 (11H, m), 1.65-1.73 (2H, m),2.55-2.75 (3H, m), 3.87-4.00 (2H, m), 6.70 (1H, dd, J=5.6 Hz, 2.4 Hz),7.14 (1H, dd, J=7.2 Hz, 7.2 Hz), 7.22 (1H, dd, J=8.8 Hz, 2.4 Hz),7.32-7.42 (3H, m), 7.60-7.67 (3H, m), 8.17 (1H, d, J=5.6 Hz), 8.32 (1H,d, J=8.8 Hz), 8.38 (1H, s), 10.12 (1H, s), 10.53 (1H, s).

Example 206N-(4-Fluorophenyl)-N′-(4-{[2-(2-oxotetrahydro-1H-1-pyrrolyl)-4-pyridyl]oxy}phenyl)urea

N-(4-Fluorophenyl)-N′-(4-{[2-(4-chlorobutyrylamino)-4-pyridyl]oxy}phenyl)urea(56 mg), potassium carbonate (46 mg) and dimethylformamide (2 ml) werestirred at 150° C. for 15 minutes. Water and ethyl acetate were addedfor extraction, and the extract was passed through a glass filter coatedwith silica gel. The silica gel was washed with ethyl acetate, and theorganic layer was distilled off under reduced pressure. Ethyl acetateand hexane were added to the residue, and the precipitated solid wasfiltered out to obtain 21 mg of a faint brown powder.

¹H-NMR (DMSO-d₆) (δppm): 1.98 (2H, tt, J=7.6 Hz, 7.6 Hz), 2.50 (2H, t,J=7.6 Hz), 3.95 (2H, t, J=7.6 Hz), 6.70 (1H, d, J=5.6 Hz), 7.05-7.15(4H, m), 7.45 (2H, dd, J=8.4 Hz, 5.2 Hz), 7.52 (2H, d, J=9.2 Hz), 7.84(1H, s), 8.22 (1H, d, J=5.6 Hz), 8.77 (1H, s), 8.83 (1H, s).

The intermediates were obtained in the following manner.

Production Example 206-14-{[2-(4-Chlorobutyrylamino)-4-pyridyl]oxy}aniline

2-Amino-4-(4-nitrophenoxy)pyridine (300 mg), 4-chlorobutyryl chloride(0.18 ml), triethylamine (0.77 ml), dimethylformamide (1 ml) andtetrahydrofuran (1 ml) were stirred at room temperature for 10 minutes,and then silica gel was added to the reaction solution, the solvent wasdistilled off under reduced pressure and the reaction product wasadsorbed onto the silica gel. The silica gel was charged into a drycolumn packed with silica gel, for column purification (hexane:ethylacetate=3:1, followed by 2:1 and 1:1). The solvent was distilled offunder reduced pressure, and then 300 mg of iron powder, 600 mg ofammonium chloride, 2 ml of DMF, 1 ml of ethanol and 1 ml of water wereadded to 150 mg of the resulting residue and the mixture was stirred at100° C. for 20 minutes. After filtration with celite, water and ethylacetate were added for extraction. The organic layer was washed 5 timeswith aqueous ammonium chloride solution and then dried over magnesiumsulfate. The drying agent was filtered off and the solvent was distilledoff under reduced pressure to obtain 110 mg of the target substance asan oil.

¹H-NMR (DMSO-d₆) δ (ppm): 1.95 (2H, tt, J=6.8 Hz, 6.8 Hz), 2.48 (2H, t,J=6.8 Hz), 3.62 (2H, t, J=6.8 Hz), 5.10 (2H, brs), 6.55 (1H, dd, J=5.6Hz, 1.2 Hz), 6.59 (2H, d, J=8.4 Hz), 6.79 (2H, d, J=8.4 Hz), 7.57 (1H,d, J=1.2 Hz), 8.09 (1H, d, J=5.6 Hz).

Production Example 206-2N-(4-Fluorophenyl)-N′-(4-{[2-(4-chlorobutyrylamino)-4-pyridyl]oxy}phenyl)urea

4-{[2-(4-Chlorobutyrylamino)-4-pyridyl]oxy}aniline (100 mg),p-fluorophenyl isocyanate (0.037 ml) and tetrahydrofuran (3 ml) werestirred at room temperature for 25 minutes. Water and ethyl acetate wereadded to the reaction solution for extraction, NH type silica gel wasadded to the extract, the solvent was distilled off under reducedpressure and the reaction product was adsorbed onto the silica gel. Thesilica gel was charged into a dry column packed with NH type silica gel,and column purification was performed (hexane:ethyl acetate=1:1,followed by ethyl acetate and ethyl acetate:methanol=10:1). The solventwas distilled off under reduced pressure to obtain 56 mg of the targetsubstance as a white solid.

¹H-NMR (DMSO-d₆) δ (ppm): 1.95 (2H, tt, J=7.2 Hz, 7.2 Hz), 2.46 (2H, t,J=7.2 Hz), 3.62 (2H, t, J=7.2 Hz), 6.63 (1H, d, J=5.6 Hz), 7.04-7.16(4H, m), 7.40-7.48 (2H, m), 7.51 (2H, d, J=8.8 Hz), 7.62 (1H, s), 8.15(1H, d, J=5.6 Hz), 8.71 (1H, s), 8.76 (1H, s), 10.52 (1H, brs).

Example 207N-[4-(2-Cyclobutanecarbonylaminopyridin-4-yl)oxyphenyl]-N′-(2-thiazolyl)urea

4-(2-Cyclobutanecarbonylaminopyridin-4-yl)oxyaniline (130 mg), phenylN-(2-thiazolyl)carbamate (110 mg) and dimethylsulfoxide (3 ml) werestirred at 80° C. for 30 minutes. Water and ethyl acetate were added tothe reaction solution for extraction, and the ethyl acetate layer waswashed 5 times with aqueous ammonium chloride solution and then driedover magnesium sulfate. The drying agent was filtered off, the solventwas distilled off under reduced pressure, ethyl acetate was added to theresidue and the precipitated solid was filtered out to obtain 130 mg ofthe target substance as a light brown solid.

¹H-NMR (DMSO-d₆) δ (ppm): 1.68 (1H, m), 1.80-1.93 (1H, m), 1.95-2.10(2H, m), 2.05-2.18 (2H, m), 3.25-3.35 (1H, m), 6.64 (1H, d, J=5.6 Hz),7.06-7.17 (3H, m), 7.36 (1H, d, J=1.6 Hz), 7.56 (2H, d, J=8.0 Hz), 7.66(1H, s), 8.14 (1H, d, J=5.6 Hz), 9.15 (1H, brs), 10.29 (1H, s).

The intermediates were obtained in the following manner.

Production Example 207-1N1-Cyclobutanecarbonyl-N1-[4-(4-nitrophenoxy)-2-pyridyl]-1-cyclobutanecarboxamide

2-Amino-4-(4-nitrophenoxy)pyridine (1.0 g), cyclobutyryl chloride (1.1g), triethylamine (1.9 ml) and tetrahydrofuran (20 ml) were stirred atroom temperature for 40 minutes. After adding water and ethyl acetatefor extraction, the extract solution was distilled off under reducedpressure and the residue was purified with a column (hexane:ethylacetate=1:1) packed with NH type silica gel. The purified product wasfurther purified by silica gel chromatography (hexane:ethyl acetate=4:1,followed by 3:1). The initially eluted substance was the targetsubstance, of which 720 mg was obtained as a colorless oil.

¹H-NMR (DMSO-d₆) δ (ppm): 1.62-1.96 (8H, m), 2.10-2.23 (4H, m),3.35-3.45 (2H, m), 7.20 (1H, d, J=5.6 Hz), 7.23 (1H, s), 7.40 (2H, d,J=9.2 Hz), 8.33 (2H, d, J=9.2 Hz), 8.49 (1H, d, J=5.6 Hz).

The second eluted substance was 2-cyclobutanecarbonylamino(4-nitrophenoxy)pyridine, of which 560 mg was obtained as whitecrystals.

¹H-NMR (DMSO-d₆) δ (ppm): 1.66-1.80 (1H, m), 1.80-1.94 (1H, m),1.98-2.20 (4H, m), 3.26-3.36 (1H, m), 6.83 (1H, d, J=5.6 Hz), 7.38 (2H,d, J=9.2 Hz), 7.81 (1H, s), 8.27 (1H, d, J=5.6 Hz), 8.31 (2H, d, J=9.2Hz).

Production Example 207-24-(4-Aminophenoxy)-2-cyclobutanecarbonylaminopyridine

N1-Cyclobutanecarbonyl-N1-[4-(4-nitrophenoxy)-2-pyridyl]-1-cyclobutanecarboxamide(720 mg), iron powder (1.4 g), ammonium chloride (2.4 g),dimethylformamide (52 ml), ethanol (2 ml) and water (2 ml) were stirredat 100° C. for 15 minutes. The mixture was filtered with celite, andthen water and ethyl acetate were added for extraction. The organiclayer was washed 5 times with aqueous ammonium chloride solution andthen dried over magnesium sulfate. The drying agent was filtered off,the solvent was distilled off under reduced pressure, ethyl acetate andhexane were added to the residue and the precipitated solid was filteredout to obtain 130 mg of a solid.

¹H-NMR (DMSO-d₆) δ (ppm): 1.68-1.80 (1H, m), 1.80-1.93 (1H, m),1.96-2.19 (4H, m), 3.23-3.34 (1H, m), 5.10 (2H, brs), 6.55 (1H, d, J=5.6Hz), 6.59 (2H, d, J=8.4 Hz), 6.79 (2H, d, J=8.4 Hz), 7.61 (1H, s), 8.07(1H, d, J=5.6 Hz), 10.22 (1H, brs).

Example 208N1-[4-{[(Cyclopropylamino)carbonyl]amino}-3-chlorophenoxy]-2-pyridyl]-1-cyclopropanecarboxamide

2-Amino-4-(4-amino-3-chlorophenoxy)pyridine (2.6 g),cyclopropanecarbonyl chloride (2.3 g), triethylamine (4.6 ml) andtetrahydrofuran (30 ml) were stirred at room temperature for 10 minutes.Water was added, extraction was performed with ethyl acetate, and themixture was dried over magnesium sulfate. The drying agent was filteredoff and the solvent was distilled off under reduced pressure to obtain3.69 g of a brown oil. A 900 mg portion of the obtained oil was stirredtogether with 0.37 ml of triethylamine and 10 ml of tetrahydrofuran,while 0.3 ml of phenyl chloroformate was added dropwise at roomtemperature. After stirring for 15 minutes, 1 ml of cyclopropylamine wasadded and stirring was continued for 22 hours. Silica gel was added tothe reaction solution, the solvent was distilled off under reducedpressure, and the reaction product was adsorbed onto the silica gel. Thesilica gel was charged into a dry column packed with silica gel, andpurification was performed by column chromatography (hexane:ethylacetate=1:1, followed by ethyl acetate) to obtain 38 mg of the targetsubstance as a brown solid.

¹H-NMR (DMSO-d₆) δ (ppm): 0.40-0.52 (2H, m), 0.60-0.70 (2H, m),0.70-0.85 (4H, m), 1.91-2.00 (1H, m), 2.50-2.70 (1H, m), 6.67 (1H, dd,J=5.6 Hz, 2.8 Hz), 7.11 (1H, dd, J=8.4 Hz, 2.8 Hz), 7.17 (1H, d, J=2.8Hz), 7.33 (1H, d, J=2.8 Hz), 7.61 (1H, d, J=2.8 Hz), 7.94 (1H, s), 8.18(1H, d, J=5.6 Hz), 8.20 (1H, d, J=8.4 Hz), 10.84 (1H, s).

The intermediates were obtained in the following manner.

Production Example 208-1 2-Amino-4-(4-amino-3-chlorophenoxy)pyridine

The publicly known compound 2-amino-4-chloropyridine (5.0 g),4-amino-3-chlorophenol (11 g), sodium hydride (60% in oil) (3.1 g) anddimethylsulfoxide (80 ml) were stirred at 160° C. for 9.5 hours. Waterwas added, extraction was performed with ethyl acetate, and the extractsolution was washed 5 times with water. The extract solution was thenpassed through a glass filter coated with silica gel. The silica gel waswashed with ethyl acetate, the ethyl acetate layers were combined, andthe solvent was distilled off under reduced pressure to obtain 5.1 g ofa dark violet solid.

¹H-NMR (DMSO-d₆) δ (ppm): 5.32 (2H, s), 5.72 (1H, s), 5.86 (2H, bs),6.07 (1H, d, J=6.4 Hz), 6.83 (2H, s), 7.01 (1H, s), 7.72 (1H, d, J=6.4Hz).

Example 209N1-[5-Bromo-4-(4-{[(cyclopropylamino)carbonyl]amino}-3-chlorophenoxy)-2-pyridyl]-1-cyclopropanecarboxamide

A mixture of 67 mg ofN1-[5-bromo-4-(4-amino-3-chlorophenoxy)-2-pyridyl]-N1-cyclopropylcarbonyl)-1-cyclopropanecarboxamide,52 mg of pyridine and 5 ml of dimethylformamide was cooled to 0° C., and54 mg of phenyl chloroformate was added. After 40 minutes, 80 mg ofcyclopropanecarbonyl chloride was added and the mixture was stirred at60° C. for 20 minutes. The mixture was returned to room temperature,water was added, and extraction was performed with ethyl acetate. Silicagel was added to the extract solution and the solvent was distilled offunder reduced pressure. The silica gel was charged into a dry columnpacked with silica gel, and purification was performed by columnchromatography (hexane:ethyl acetate=1:1). Methanol was added to theresidue to obtain 11 mg of the target substance as a white solid.

¹H-NMR (DMSO-d₆) δ (ppm): 0.40 (2H, brs), 0.65 (2H, m), 0.72 (4H, brs),1.90 (1H, brs), 2.55 (1H, brs), 7.11 (1H, d, J=9.2 Hz), 7.19 (1H, s),7.38 (1H, s), 7.56 (1H, s), 7.96 (1H, s), 8.22 (1H, d, J=9.2 Hz), 8.42(1H, s), 10.94 (1H, s).

The intermediates were obtained in the following manner.

Production Example 209-12-Amino-3-bromo-4-(4-amino-3-chlorophenoxy)pyridine

2-Amino-4-(4-amino-3-chlorophenoxy)pyridine (1.0 g), N-bromosuccinimide(0.78 g) and isopropanol (10 ml) were stirred for 15 minutes underreflux. The mixture was returned to room temperature, water was added,and extraction was performed with ethyl acetate. Silica gel was added tothe extract solution and the solvent was distilled off under reducedpressure. The silica gel was charged into a dry column packed withsilica gel, and purification was performed by column chromatography(hexane:ethyl acetate=2:1, followed by 1:1, ethyl acetate) to obtain 400mg of the target substance as a brown oil.

¹H-NMR (DMSO-d₆) δ (ppm): 5.39 (2H, brs), 5.68 (1H, s), 6.06 (2H, brs),6.85 (1H, s), 6.86 (1H, d, J=2.4 Hz), 7.09 (1H, d, J=2.4 Hz), 7.90 (1H,s).

Production Example 209-2N1-[5-Bromo-4-(4-amino-3-chlorophenoxy)-2-pyridyl]-N1-cyclopropylcarbonyl)-1-cyclopropanecarboxamide

Cyclopropanecarbonyl chloride (260 mg) was added to a solution of 400 mgof 2-amino-3-bromo-4-(4-amino-3-chlorophenoxy)pyridine, 0.53 ml oftriethylamine and 5 ml of tetrahydrofuran while stirring at roomtemperature. After 40 minutes, silica gel was added to the reactionsolution and the solvent was distilled off under reduced pressure. Thesilica gel was charged into a dry column packed with silica gel, andpurification was performed by column chromatography (hexane:ethylacetate=2:1, followed by 1:1, ethyl acetate) to obtain 67 mg of thetarget substance.

¹H-NMR (DMSO-d₆) δ (ppm): 0.66-1.00 (8H, m), 1.85-1.96 (2H, m), 5.45(2H, brs), 6.77 (1H, s), 6.84 (1H, d, J=8.8 Hz), 6.92 (1H, dd, J=8.8 Hz,2.8 Hz), 7.17 (1H, d, J=2.8 Hz), 8.66 (1H, s).

Example 210N1-[4-(3,5-Dichloro-4-{[(cyclopropylamino)carbonyl]amino}phenoxy)-2-pyridyl]-1-cyclopropanecarboxamide

Phenylchloroformate (110 mg) was added to a solution 96 mg ofN1-[4-(4-amino-3,5-dichlorophenoxy)-2-pyridyl]-N1-cyclopropylcarbonyl)-1-cyclopropanecarboxamide,0.076 ml of pyridine and 5 ml of dimethylformamide while stirring. Aftercontinuing stirring for 30 minutes, 0.5 ml of cyclopropylamine was addedand the mixture was heated at 70° C. for 10 minutes. The mixture wasreturned to room temperature, water was added, and extraction wasperformed with ethyl acetate. Silica gel was added to the extractsolution and the solvent was distilled off under reduced pressure. Thesilica gel was charged into a dry column packed with silica gel, andpurification was performed by column chromatography (ethyl acetate).Methanol was added to the residue for solidification to obtain 4.8 mg ofthe target substance as a light brown solid.

¹H-NMR (DMSO-d₆) δ (ppm): 0.42 (2H, s), 0.57-0.66 (2H, m), 0.70-0.83(4H, m), 1.92-2.01 (1H, m), 2.43-2.53 (1H, m), 6.62 (1H, s), 6.71 (1H,d, J=5.6 Hz), 7.39 (2H, s), 7.69 (1H, s), 7.89 (1H, s), 8.22 (1H, d,J=5.6 Hz), 10.89 (1H, s).

The intermediates were obtained in the following manner.

Production Example 210-1 2-Amino-4-(4-amino-3,5-dichlorophenoxy)pyridine

2-Amino-4-(4-amino-3-chlorophenoxy)pyridine (700 mg),N-chlorosuccinimide (0.44 g) and isopropanol (10 ml) were stirred at 80°C. for 1 hour. The mixture was returned to room temperature, water wasadded, and extraction was performed with ethyl acetate. Silica gel wasadded to the extract solution and the solvent was distilled off underreduced pressure. The silica gel was charged into a dry column packedwith silica gel, and purification was performed by column chromatography(ethyl acetate), to obtain 120 mg of a brown oil.

¹H-NMR (DMSO-d₆) δ (ppm): 5.47 (2H, brs), 5.73 (1H, d, J=2.4 Hz), 5.90(2H, brs), 6.09 (1H, dd, J=5.6 Hz, 2.4 Hz), 7.13 (2H, s), 7.75 (1H, d,J=5.6 Hz).

Production Example 210-2N1-[4-(4-Amino-3,5-dichlorophenoxy)-2-pyridyl]-N1-cyclopropylcarbonyl)-1-cyclopropanecarboxamide

Cyclopropanecarbonyl chloride (93 mg) was added to a solution of 120 mgof 2-amino-4-(4-amino-3,5-dichlorophenoxy)pyridine, 0.19 ml oftriethylamine and 5 ml of tetrahydrofuran while stirring at roomtemperature. After 20 minutes, silica gel was added to the reactionsolution and the solvent was distilled off under reduced pressure. Thesilica gel was charged into a dry column packed with silica gel, andpurification was performed by column chromatography (ethyl acetate) toobtain 120 mg of a brown oil.

¹H-NMR (DMSO-d₆) δ (ppm): 0.82-0.98 (8H, m), 1.86-1.96 (2H, m), 5.55(2H, brs), 6.95 (1H, dd, J=5.6 Hz, 2.4 Hz), 7.03 (1H, d, J=2.4 Hz), 7.24(2H, s), 8.38 (1H, d, J=5.6 Hz).

Example 211N1-Cyclopropyl-5-({2-[di(cyclopropylcarbonyl)amino]-4-pyridyl}oxy)-1H-1-indolecarboxamide

Cyclopropanecarbonyl chloride (51 mg) was added to a solution of 100 mgof N1-cyclopropyl-5-[(2-amino-4-pyridyl)oxy]-1H-1-indolecarboxamide and49 mg of triethylamine in tetrahydrofuran at 0° C. After 20 minutes ofstirring, silica gel was added to the reaction solution, the solvent wasdistilled off under reduced pressure, and the reaction product wasadsorbed onto the silica gel. The silica gel was charged into a drycolumn packed with silica gel, and purification was performed by columnchromatography (hexane:ethyl acetate=1:1, followed by ethyl acetate),after which water was added to the residue to obtain 19 mg of the targetsubstance as a white solid.

¹H-NMR (DMSO-d₆) δ (ppm): 0.57-0.63 (2H, m), 0.68-0.75 (2H, m),0.83-0.96 (6H, m), 1.86-1.94 (2H, m), 2.73-2.80 (1H, m), 6.66 (1H, d,J=3.6 Hz), 6.91 (1H, d, J=5.6 Hz), 6.98 (1H, d, J=2.4 Hz), 7.08 (1H, dd,J=9.2 Hz, 2.4 Hz), 7.41 (1H, d, J=2.4 Hz), 7.87 (1H, d, J=3.6 Hz),8.26-8.32 (2H, m), 8.38 (1H, d, J=5.6 Hz).

The intermediates were obtained in the following manner.

Production Example 211-1 5-[(2-Amino-4-pyridyl)oxy]-1H-indole

2-Amino-4-chloropyridine (2.0 g), 5-hydroxyindole (4.1 g), sodiumhydride (60% in oil, 1.25 g) and dimethylsulfoxide (20 ml) were stirredat 160° C. for 9.5 hours. Water was added, extraction was performed withethyl acetate, and purification was performed by silica gel columnchromatography (hexane:ethyl acetate=1:1, ethylacetate). The solvent wasdistilled off under reduced pressure, a small amount of ethyl acetatewas added to the residue and the solid was filtered out to obtain 490 mgof a light brown solid.

¹H-NMR (DMSO-d₆) δ (ppm): 5.72 (1H, d, J=2.0 Hz), 5.78 (2H, brs), 6.10(1H, d, J=5.6 Hz), 6.41 (1H, d, J=2.0 Hz), 6.82 (1H, d, J=8.4 Hz), 7.25(1H, s), 7.36-7.7.44 (2H, m), 7.73 (1H, d, J=5.6 Hz), 11.15 (1H, s).

Production Example 211-2N1-Cyclopropyl-5-[(2-amino-4-pyridyl)oxy]-1H-1-indolecarboxamide

After adding 28 mg of sodium hydride (60% in oil) to a solution of 150mg of 5-[(2-amino-4-pyridyl)oxy]-1H-indole in dimethylformamide at roomtemperature and stirring for 5 minutes, the mixture was cooled to 0° C.,124 mg of phenyl N-cyclopropylcarbamate was added and the mixture wasfurther stirred for 30 minutes. Water was added, extraction wasperformed with ethyl acetate, the organic layer was washed 3 times withwater and once with aqueous ammonium chloride solution, and then silicagel was added and the solvent was distilled off under reduced pressure.The silica gel was charged into a dry column packed with silica gel andpurification was performed by column chromatography (hexane:ethylacetate=1:1, followed by ethyl acetate), to obtain 2.4 g of a colorlesspowder.

¹H-NMR (DMSO-d₆) δ (ppm): 0.57-0.64 (2H, m), 0.68-0.76 (2H, m),2.72-2.79 (1H, m), 5.74 (1H, d, J=2.4 Hz), 5.83 (2H, brs), 6.12 (1H, dd,J=5.6 Hz, 2.4 Hz), 6.64 (1H, d, J=3.6 Hz), 7.01 (1H, dd, J=9.2 Hz, 2.4Hz), 7.32 (1H, d, J=2.4 Hz), 7.75 (1H, d, J=5.6 Hz), 7.84 (1H, d, J=3.6Hz), 8.24 (1H, s), 8.25 (1H, d, J=9.2 Hz).

Example 212N1-Cyclopropyl-5-({2-[(cyclopropylcarbonyl)amino]-4-pyridyl}oxy)-1H-1-indolecarboxamide

N1-Cyclopropyl-5-({2-[di(cyclopropylcarbonyl)amino]-4-pyridyl}oxy)-1H-1-indolecarboxamide(190 mg), ammonium chloride (660 mg), dimethylformamide (5 ml), water (5ml) and ethanol (5 ml) were stirred at 100° C. for 1 hour. Water andethyl acetate were added for extraction, and the extract was washed 6times with water. After drying over magnesium sulfate, the drying agentwas filtered off and the solvent was distilled off under reducedpressure. Ethyl acetate was added to the residue and the precipitatedsolid was filtered out to obtain 66 mg of a white powder.

¹H-NMR (DMSO-d₆) δ (ppm): 0.57-0.64 (2H, m), 0.66-0.78 (6H, m),1.88-1.98 (1H, m), 2.72-2.80 (1H, m), 6.63-6.69 (2H, m), 7.04 (1H, d,J=8.8 Hz), 7.36 (1H, s), 7.56 (1H, s), 7.87 (1H, d, J=3.6 Hz), 8.14 (1H,d, J=5.6 Hz), 8.26 (1H, d, J=8.8 Hz), 8.28 (1H, s), 10.55 (1H, s).

Example 213N1-Cyclopropyl-5-{[2-(2,5-dioxotetrahydro-1H-1-pyrrolyl)-4-pyridyl]oxy}-1H-1-indolecarboxamide(Example 213-A)N1-Cyclopropyl-5-{[2-(diacetylamino)-4-pyridyl]oxy}-1H-1-indolecarboxamide(Example 213-B)N1-Cyclopropyl-5-{[2-(acetylamino)-4-pyridyl]oxy}-1H-1-indolecarboxamide(Example 213-C)

N1-Cyclopropyl-5-[(2-amino-4-pyridyl)oxy]-1H-1-indolecarboxamide (830mg), succinic anhydride (270 mg) and toluene (30 ml) were refluxedtogether for 30 minutes. After adding 50 ml of acetic anhydride and 82mg of sodium acetate to the reaction solution, the mixture was stirredat 80° C. for 15 minutes. The solvent was distilled off under reducedpressure, and the residue was purified by silica gel chromatography(ethyl acetate). The second eluted substance wasN1-cyclopropyl-5-{[2-(2,5-dioxotetrahydro-1H-1-pyrrolyl)-4-pyridyl]oxy}-1H-1-indolecarboxamide,of which 440 mg was obtained as a colorless powder.

Example 213-A

¹H-NMR (DMSO-d₆) δ (ppm): 0.57-0.63 (2H, m), 0.70-0.75 (2H, m),2.70-2.80 (1H, m), 2.71 (4H, s), 6.66 (1H, d, J=3.6 Hz), 6.76 (1H, d,J=2.4 Hz), 7.03 (1H, dd, J=5.6 Hz, 2.4 Hz), 7.10 (1H, dd, J=9.2 Hz, 2.4Hz), 7.43 (1H, d, J=2.4 Hz), 7.87 (1H, d, J=3.6 Hz), 8.29 (1H, s), 8.30(1H, d, J=9.2 Hz), 8.42 (1H, d, J=5.6 Hz).

The first eluted substance was a mixture ofN1-cyclopropyl-5-{[2-(diacetylamino)-4-pyridyl]oxy}-1H-1-indolecarboxamideandN1-cyclopropyl-5-{[2-(acetylamino)-4-pyridyl]oxy}-1H-1-indolecarboxamide.The mixture was purified by silica gel chromatography(chloroform:methanol=50:1). The first eluted substance wasN1-cyclopropyl-5-{[2-(diacetylamino)-4-pyridyl]oxy}-1H-1-indolecarboxamide,of which 45 mg was obtained as a white powder.

Example 213-B

¹H-NMR (DMSO-d₆) δ (ppm): 0.57-0.63 (2H, m), 0.70-0.75 (2H, m), 2.13(6H, s), 2.74-2.80 (1H, m), 6.66 (1H, d, J=3.6 Hz), 6.96 (1H, dd, J=5.6Hz, 2.4 Hz), 6.99 (1H, d, J=2.4 Hz), 7.09 (1H, dd, J=9.2 Hz, 2.4 Hz),7.43 (1H, d, J=2.4 Hz), 7.87 (1H, d, J=3.6 Hz), 8.28 (1H, s), 8.30 (1H,d, J=9.2 Hz), 8.38 (1H, d, J=5.6 Hz).

The second eluted substance wasN1-cyclopropyl-5-{[2-(acetylamino)-4-pyridyl]oxy}-1H-1-indolecarboxamide,which was solidified from ethyl acetate-hexane to obtain 28 mg.

Example 213-C

¹H-NMR (DMSO-d₆) δ (ppm): 0.57-0.63 (2H, m), 0.70-0.75 (2H, m), 2.00(3H, s), 2.72-2.80 (1H, m), 6.62 (1H, d, J=5.6 Hz, 2.4 Hz), 6.65 (1H, d,J=3.6 Hz), 7.04 (1H, dd, J=9.2 Hz, 2.4 Hz), 7.36 (1H, d, J=2.4 Hz), 7.60(1H, s), 7.87 (1H, d, J=3.6 Hz), 8.13 (1H, d, J=9.2H), 8.25-8.30 (2H,m), 10.47 (1H, s).

Example 214N1-Cyclopropyl-5-{[2-({[2-chloroethylamino]carbonyl}amino)-4-pyridyl]oxy}-1H-1-indolecarboxamide

N1-cyclopropyl-5-[(2-amino-4-pyridyl)oxy]-1H-1-indolecarboxamide (400mg), 2-chloroethylisocyanate (150 mg) and tetrahydrofuran (5 ml) werestirred at 80° C. for 1.5 hours. The mixture was returned to roomtemperature, silica gel was added, and the solvent was distilled offunder reduced pressure. The silica gel was charged into a dry columnpacked with silica gel, and purification was performed by columnchromatography (hexane:ethyl acetate=1:1, followed by ethyl acetate) toobtain 280 mg of a colorless powder.

¹H-NMR (DMSO-d₆) δ (ppm): 0.57-0.63 (2H, m), 0.70-0.75 (2H, m),2.73-2.80 (1H, m), 3.42 (2H, q, J=6.0 Hz), 3.61 (2H, t, J=6.0 Hz), 6.52(1H, dd, J=5.6 Hz, 2.4 Hz), 6.65 (1H, d, J=3.6 Hz), 6.85 (1H, d, J=2.4Hz), 7.04 (1H, dd, J=8.8 Hz, 2.4 Hz), 7.35 (1H, d, J=2.4 Hz), 7.86 (1H,d, J=3.6 Hz), 8.04 (1H, d, J=5.6 Hz), 8.27 (1H, s), 8.28 (1H, d, J=8.8Hz), 8.34 (1H, brs), 9.19 (1H, s).

Example 215N1-(2-Fluoroethyl)-5-({2-[(cyclopropylcarbonyl)amino]-4-pyridyl}oxy)-1H-1-indolecarboxyamide

Cyclopropanecarbonyl chloride (330 mg) was added to a solution of 400 mgof N1-(2-fluoroethyl)-5-[(2-amino-4-pyridyl)oxy]-1H-1-indolecarboxamideand 0.53 ml of triethylamine in tetrahydrofuran at room temperature.After stirring for 15 minutes, water and ethyl acetate were added forextraction. The extract was dried over magnesium sulfate and then passedthrough a glass filter coated with silica gel. The solvent was distilledoff under reduced pressure to obtain 490 mg of an oil. After adding 1.5g of ammonium chloride, 10 ml of dimethylformamide, 10 ml of water and10 ml of ethanol to the residue, the mixture was stirred at 110° C. for1.5 hours. After returning it to room temperature, water was added andextraction was performed with ethyl acetate. Silica gel was added to theextract solution, and the solvent was distilled off under reducedpressure for adsorption onto the silica gel. The silica gel was chargedinto a dry column packed with silica gel and purification was performedby column chromatography (ethyl acetate). Ethyl acetate and hexane wereadded to the residue for solidification to obtain 180 mg of the targetsubstance as a white solid.

¹H-NMR (DMSO-d₆) δ (ppm): 0.64-0.80 (4H, m), 1.88-1.97 (1H, m),3.50-3.65 (2H, m), 4.52 (1H, t, J=4.8 Hz), 4.64 (1H, t, J=4.8 Hz), 6.65(1H, dd, J=5.6 Hz, 2.4 Hz), 6.69 (1H, d, J=3.6 Hz), 7.05 (1H, dd, J=8.8Hz, 2.4 Hz), 7.38 (1H, d, J=2.4 Hz), 7.57 (1H, d, J=2.4 Hz), 7.95 (1H,d, J=3.6 Hz), 8.14 (1H, d, J=5.6 Hz), 8.27 (1H, d, J=8.8 Hz), 8.47 (1H,t, J=5.6 Hz), 10.77 (1H, s).

The intermediates were obtained in the following manner.

Production Example 215-1N1-(2-Fluoroethyl)-5-[(2-amino-4-pyridyl)oxy]-1H-1-indolecarboxamide

Sodium hydride (60% in oil) (360 mg) was added to a solution of 2.0 g of5-[(2-amino-4-pyridyl)oxy]-1H-indole in 30 ml of dimethylformamide atroom temperature. After stirring for 5 minutes, the mixture was placedin an ice bath and 1.8 g of phenyl N-(2-fluoroethyl)carbamate was addedwhile cooling. The mixture was returned to room temperature and stirredfor 30 minutes, after which water was added and extraction was performedwith ethyl acetate. The extract was passed through a glass filter coatedwith silica gel. The ethyl acetate layer was washed once with sodiumbicarbonate water and dried over magnesium sulfate. The drying agent wasfiltered off to obtain 1.93 g of a faint brown powder.

¹H-NMR (DMSO-d₆) δ (ppm): 3.52-3.64 (2H, m), 4.52 (1H, t, J=4.8 Hz),4.64 (1H, t, J=4.8 Hz), 5.75 (1H, d, J=2.4 Hz), 5.82 (2H, brs), 6.12(1H, dd, J=5.6 Hz, 2.4 Hz), 6.68 (1H, d, J=3.6 Hz), 7.02 (1H, dd, J=8.8Hz, 2.4 Hz), 7.33 (1H, d, J=2.4 Hz), 7.76 (1H, d, J=5.6 Hz), 7.92 (1H,d, J=3.6 Hz), 8.26 (1H, d, J=8.8 Hz), 8.44 (1H, t, J=5.2 Hz).

Example 216N1-Cyclopropyl-5-(4-{[2-(2-oxotetrahydro-1H-1-pyrrolyl)-4-pyridyl]oxy}-1H-1-indolecarboxamide

Sodium hydride (60% in oil) (19 mg) was added to a solution of 130 mg of5-(4-{[2-(2-oxotetrahydro-1H-1-pyrrolyl)-4-pyridyl]oxy}-1H-1-indole indimethylformamide at room temperature, and then 82 mg of phenylN-cyclopropylcarbamate was added. After stirring for 10 minutes, waterwas added and extraction was performed with ethyl acetate. Silica gelwas added to the extract solution and the solvent was distilled off foradsorption onto the silica gel. The silica gel was charged into a drycolumn packed with silica gel and purification was performed by columnchromatography (hexane:ethyl acetate=1:1, followed by ethyl acetate).Ethyl acetate and hexane were added to the residue for solidification toobtain 25 mg of the target substance as a white solid.

¹H-NMR (DMSO-d₆) δ (ppm): 0.58-0.63 (2H, m), 0.68-0.75 (2H, m), 1.97(2H, tt, J=6.4 Hz, 6.4 Hz), 2.47 (2H, t, J=6.4 Hz), 2.73-2.80 (1H, m),3.94 (2H, t, J=6.4 Hz), 6.65 (1H, d, J=3.6 Hz), 6.71 (1H, dd, J=5.6 Hz,2.4 Hz), 7.04 (1H, dd, J=8.8 Hz, 2.4 Hz), 7.36 (1H, d, J=2.4 Hz), 7.81(1H, d, J=2.4 Hz), 7.86 (1H, d, J=3.6 Hz), 8.22 (1H, d, J=5.6 Hz), 8.27(1H, brs), 8.28 (1H, d, J=8.8 Hz).

The intermediates were obtained in the following manner.

Production Example 216-15-(4-{[2-(2-Oxotetrahydro-1H-1-pyrrolyl)-4-pyridyl]oxy}-1H-1-indole

4-Bromobutyryl chloride (0.8 ml) was added to a solution of 1.0 g ofN1-cyclopropyl-5-[(2-amino-4-pyridyl)oxy]-1H-1-indolecarboxamide, 1.1 mlof triethylamine and 20 ml of tetrahydrofuran at room temperature. Afterstirring for 20 minutes, water was added and extraction was performedwith ethyl acetate. The extract was passed through a glass filter coatedwith silica gel. After adding 950 mg of 4-hydroxypiperidine, 1.7 g ofpotassium carbonate and 10 ml of dimethylformamide to the obtained oil,the mixture was stirred at 70° C. for 20 minutes. Water was added,extraction was performed with ethyl acetate, silica gel was added to theextract solution, and the solvent was distilled off under reducedpressure for adsorption onto the silica gel. The silica gel was chargedinto a dry column packed with silica gel and purification was performedby column chromatography (hexane:ethyl acetate=1:1, followed by ethylacetate). The first eluted substance was the target substance, of which130 mg was obtained as a white solid.

¹H-NMR (DMSO-d₆) δ (ppm): 1.97 (2H, tt, J=6.4 Hz, 6.4 Hz), 2.46 (2H, t,J=6.4 Hz), 3.93 (2H, t, J=6.4 Hz), 6.42 (1H, s), 6.66 (1H, d, J=5.6 Hz),6.85 (1H, d, J=8.8 Hz), 7.29 (1H, s), 7.42 (1H, s), 7.44 (1H, d, J=8.8Hz), 7.80 (1H, s), 8.18 (1H, d, J=5.6 Hz), 11.05 (1H, s).

The second eluted substance was5-[(2-{[4-(4-hydroxypiperidino)butanoyl]amino}-4-pyridyl)oxy]indole, ofwhich 520 mg was obtained as a light brown oil.

¹H-NMR (DMSO-d₆) δ (ppm): 1.25-1.35 (2H, m), 1.55-1.67 (4H, m),1.85-1.95 (2H, m), 2.17 (2H, t, J=6.8 Hz), 2.28 (2H, t, J=6.8 Hz),2.57-2.67 (2H, m), 3.15 (1, d, J=3.6 Hz), 3.30-3.42 (1H, m), 4.48 (1H,d, J=3.6 Hz), 6.42 (1H, s), 6.57 (1H, dd, J=5.6 Hz, 2.4 Hz), 6.85 (1H,dd, J=8.8 Hz, 2.4 Hz), 7.29 (1H, d, J=2.4 Hz), 7.40-7.43 (2H, m), 7.60(1H, d, J=2.4 Hz), 8.09 (1H, d, J=5.6 Hz), 10.37 (1H, s), 11.23 (1H, s).

Example 2171-(4-[6-Cyano-7-(3-diethylaminopropoxy)-4-quinolyloxy]2-fluorophenyl)-3-(4-fluorophenyl)urea

After dissolving 480 mg of6-cyano-4-{4-[4-fluoroanilinocarbonyl]amino-3-fluorophenoxy}quinolin-7-olsodium salt in 5 ml of dimethylformamide, 350 mg of potassium carbonateand 204 mg of 3-chloropropyldiethylamine were added and the mixture washeated and stirred at 65° C. for 7 hours. After standing to cool, waterwas added and extraction was performed with ethyl acetate andtetrahydrofuran, after which the solvent was distilled off under reducedpressure and the residue was purified by NH silica gel columnchromatography (ethyl acetate-methanol system) to obtain 135 mg of thetitle compound.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.96 (6H, t, J=7.0 Hz) 1.93 (2H,quint, J=7.0 Hz), 2.45-2.53 (4H, m), 2.61 (2H, t, J=7.0 Hz), 4.32 (2H,t, J=7.0 Hz), 6.62 (1H, d, J=5.3 Hz), 7.10-7.19 (3H, m), 7.41 (1H, dd,J=12.3 Hz, J′=2.8 Hz), 7.46-7.52 (2H, m), 7.60 (1H, s), 8.25 (1H, t,J=9.0 Hz), 8.68 (1H, d, J=2.0 Hz), 8.76-8.78 (2H, m), 9.16 (1H, s)

The intermediates were synthesized in the following manner.

Production Example 217-11-(4-[7-Benzyloxy-6-cyano-4-quinolyloxy]-2-fluorophenyl)-3-(4-fluorophenyl)urea

After adding 210 mg of toluene and 20 ml of acetonitrile to 6.95 g ofthe 7-benzyloxy-6-cyano-4-(3-fluoro-4-aminophenoxy)quinoline obtained inProduction Example 8, the mixture was heated to reflux. Next, 2.67 ml of4-fluorophenyl isocyanate was added and the mixture was further heatedto reflux for 1 hour. After cooling, the precipitated solid was filteredout and dried under reduced pressure to obtain 7.45 g of the titlecompound.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 5.49 (2H, s), 6.61 (1H, d, J=5.4 Hz),7.05-7.57 (11H, m), 7.54 (1H, s), 8.24 (1H, t, 9.5 Hz), 8.63 (1H, s),8.72 (1H, d, J=5.4 Hz), 8.77 (1H, s), 9.10 (1H, s)

Production Example 217-26-Cyano-4-(4-[4-fluoroanilinocarbonyl]amino-3-fluorophenoxy)quinolin-7-olsodium salt

A mixture of 1.7 g of1-(4-[7-benzyloxy-6-cyanoquinolin-4-yloxy]-2-fluorophenyl)-3-(4-fluorophenyl)urea,17 ml of trifluoroacetic acid and 1.7 ml of thioanisole was placed in anoil bath and heated and stirred for 20 hours at 70° C. After completionof the reaction, the reaction solution was concentrated, a saturatedaqueous sodium bicarbonate solution and methanol were added, the mixturewas stirred for 30 minutes, and the precipitated solid was filtered out.The obtained solid was dried under reduced pressure to obtain 1.15 g ofthe title compound.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 6.62 (1H, d, J=5.3 Hz), 7.18-7.68(7H, m), 8.24 (1H, t, J=8.5 Hz), 8.70-8.86 (3H, m), 9.20 (1H, s)

Example 2181-(4-[6-Cyano-7-(3-morpholine-4-propoxyl)-4-quinolyloxy]-2-fluorophenyl)-3-(4-fluorophenyl)urea

The title compound (205 mg) was obtained using 450 mg of6-cyano-4-(4-[4-fluoroanilinocarbonyl]amino-3-fluorophenoxy)quinolin-7-olsodium salt, 5 ml of dimethylformamide, 328 mg of potassium carbonateand 194 mg of 4-(3-chloropropyl)morpholine, in the same manner asExample 217.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.01 (2H, quint, J=6.9 Hz), 2.36-2.44(4H, m), 2.48-2.54 (2H, covered by DMSO peak), 3.58 (4H, t, J=4.0 Hz),4.35 (2H, t, J=6.9 Hz), 6.64 (1H, d, J=5.3 Hz), 7.10-7.19 (3H, m), 7.41(1H, dd, J=2.9, 12.3 Hz), 7.44-7.52 (2H, m), 7.63 (1H, s), 8.25 (1H, t,J=8.9 Hz), 8.64 (1H, d, J=2.0 Hz), 8.74-8.78 (2H, m), 9.20 (1H, s)

Example 2191-(4-[6-Cyano-7-(3-diethylaminopropoxy)-4-quinolyloxy]-2-fluorophenyl)-3-phenylurea

After dissolving 179 mg of6-cyano-4-(4-[4-anilinocarbonylamino]-3-phenoxy)quinolin-7-ol sodiumsalt in 2 ml of dimethylformamide, 135 mg of potassium carbonate and 79mg of 3-chloropropyldiethylamine were added and the mixture was heatedand stirred overnight at 65-75° C. After standing to cool, water wasadded, extraction was performed with ethyl acetate and tetrahydrofuranand the extract was dried over sodium sulfate, after which the solventwas distilled off under reduced pressure and the residue was purified byNH silica gel column chromatography (ethyl acetate-methanol system) toobtain 60 mg of the title compound.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.94 (6H, t, J=7.2 Hz) 1.92 (2H,quint, J=7.2 Hz), 2.43-2.55 (4H, covered by DMSO peak), 2.60 (2H, t,J=7.2 Hz), 4.42 (2H, t, J=7.2 Hz), 6.62 (1H, d, J=5.0 Hz), 6.98 (1H, t,J=7.2 Hz), 7.12-7.18 (1H, m), 7.29 (2H, t, J=7.2 Hz), 7.40 (1H, dd,J=11.9 Hz, J′=2.8 Hz), 7.46 (2H, d, J=7.2 Hz), 7.59 (1H, s), 8.26 (1H,t, J=9.0 Hz), 8.67 (1H, s), 8.72-8.78 (2H, m), 9.16 (1H, s)

The intermediates were synthesized in the following manner.

Production Example 219-11-(4-[7-Benzyloxy-6-cyano-4-quinolyloxy]-2-fluorophenyl)-3-phenylurea

After adding 1.90 g of the7-benzyloxy-6-cyano-4-(3-fluoro-4-aminophenoxy)quinoline obtained inProduction Example 8 to 60 ml of toluene and 30 ml of acetonitrile, themixture was heated to reflux. Next, 0.76 ml of phenyl isocyanate wasadded and the mixture was further heated to reflux for 1 hour. Aftercooling, the precipitated solid was filtered out and dried under reducedpressure to obtain 1.65 g of the title compound.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 5.45 (2H, s), 6.62 (1H, d, J=5.4 Hz),6.95-7.57 (12H, m), 7.71 (1H, s), 8.27 (1H, t, 9.2 Hz), 8.66 (1H, s),8.74 (1H, d, J=5.4 Hz), 8.78 (1H, s), 9.09 (1H, s)

Production Example 219-26-Cyano-4-(4-[4-anilinocarbonylamino]-3-fluorophenoxy)quinolin-7-olsodium salt

A mixture of 1.64 g of1-(4-[7-benzyloxy-6-cyano-4-quinolyloxy]-2-fluorophenyl)-3-phenylurea,16 ml of trifluoroacetic acid and 1.6 ml of thioanisole was placed in anoil bath and heated to reflux at 65-72° C. for 14 hours. Aftercompletion of the reaction, the reaction solution was concentrated, asaturated aqueous sodium bicarbonate solution and methanol were added,the mixture was stirred for 30 minutes, and the precipitated solid wasfiltered out. The obtained solid was dried under reduced pressure toobtain 1.35 g of the title compound.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 6.41 (1H, d, J=5.1 Hz), 6.98 (1H, t,J=7.1 Hz), 7.11 (1H, d, J=7.1 Hz), 7.20-7.40 (4H, m), 7.45 (2H, d, J=7.1Hz), 8.24 (1H, t, J=8.0 Hz), 8.55 (1H, s), 8.57 (1H, d, J=5.1 Hz), 8.66(1H, s), 9.10 (1H, s),

Example 2201-{4-[6-Cyano-7-(3-morpholino-4-propoxyl)-4-quinolyloxy]-2-fluorophenyl}-3-phenylurea

The title compound (301 mg) was obtained using 505 mg of6-cyano-4-(4-[4-anilinocarbonylamino]-3-phenoxy)-quinolin-7-ol sodiumsalt, 5 ml of dimethylformamide, 380 mg of potassium carbonate and 195mg of 4-(3-chloropropyl)morpholine, in the same manner as Example 217.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.99 (2H, quint, J=6.8 Hz), 2.33-2.52(4H, m), 2.48-2.54 (2H, covered by DMSO peak), 3.58 (4H, t, J=4.2 Hz),4.32 (2H, t, J=6.8 Hz), 6.62 (1H, d, J=5.3 Hz), 6.98 (1H, t, J=7.2 Hz),7.12-7.48 (6H, m), 7.60 (1H, s), 8.26 (1H, t, J=8.5 Hz), 8.64 (1H, d,J=1.5 Hz), 8.72-8.78 (2H, m), 9.06 (1H, s)

Example 221N-[4-(6-Cyano-7-[3-(dimethylamino)propoxy]-4-quinolyloxy)phenyl]-N′-(4-fluorophenyl)urea

The title compound (20 mg) was obtained from 100 mg of6-cyano-4-(4-[(4-fluoroanilino)carbonyl]aminophenoxy)quinolin-7-olsodium salt, by the same procedure as in Example 7.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.97 (2H, quint, J=7.1 Hz) 2.18 (6H,s,), 2.42 (2H, t, J=7.1 Hz), 4.32 (2H, t, J=7.1 Hz), 6.54 (1H, d, J=5.6Hz), 7.05-7.65 (9H, m), 8.63 (1H, d, J=5.6 Hz), 8.76 (1H, s) 8.80 (1H,s). 8.88 (1H, s)

Example 222N-(5-(6,7-Dimethoxyquinolin-4-yloxy)pyridin-2-yl)-N′-phenylurea

5-(6,7-Dimethoxyquinolin-4-yloxy)pyridin-2-ylamine (29.7 mg, 0.100 mmol)and phenyl isocyanate (13.1 mg, 0.110 mmol) were stirred indimethylformamide (1 ml) at room temperature for 18 hours. The reactionsolution was distributed between ethyl acetate and water, the organiclayer was washed with water and saturated brine and dried over anhydrousmagnesium sulfate, the drying agent was filtered off and the filtratewas distilled off under reduced pressure. The obtained crude product wassubjected to silica gel column chromatography (eluent—ethylacetate:methanol=20:1), and the fraction containing the target substancewas concentrated, suspended in ethyl acetate and diluted with hexane,after which the crystals were filtered out, washed with hexane and thenblow-dried to obtain the title compound (30.4 mg, 0.073 mmol, 73%) ascolorless crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.95 (3H, s), 3.96 (3H, s), 6.53 (1H,d, J=5.4 Hz), 7.00-7.06 (1H, m), 7.28-7.35 (2H, m), 7.41 (1H, s),7.50-7.56 (3H, m), 7.76-7.82 (2H, m), 8.30-8.33 (1H, m), 8.49 (1H, d,J=5.4 Hz), 9.56 (1H, s), 10.04 (1H, s).

The intermediates were synthesized in the following manner.

Production Example 222-1 2-Chloro-6-iodopyridin-3-ol

After dissolving 2-chloro-3-hydroxypyridine (5.00 g, 38.6 mmol) andsodium iodide (5.79 g, 38.6 mmol) in dimethylformamide (70 ml),Chloramine T (10.9 g, 38.6 mmol) was added while cooling on ice, andthen the mixture was stirred at room temperature for 1 hour. Upon adding2N aqueous hydrochloric acid (19.3 ml, 38.6 mmol) after the reaction,the reaction solution was distributed between ethyl acetate and water,the organic layer was washed with water and saturated brine and driedover anhydrous magnesium sulfate, the drying agent was filtered off andthe filtrate was distilled off under reduced pressure. The obtainedcrude product was subjected to silica gel column chromatography(eluent—ethyl acetate:hexane=1:2), and the fraction containing thetarget substance was concentrated to obtain the title compound (9.00 g,35.2 mmol, 91%) as colorless crystals.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 5.61 (1H, br s), 7.02 (1H, d, J=8.2Hz), 7.56 (1H, d, J=8.2 Hz).

Production Example 222-24-(2-Chloro-6-iodopyridin-3-yloxy)-6,7-dimethoxyquinoline

4-Chloro-6,7-dimethoxyquinoline (2.23 g, 10.0 mmol),2-chloro-6-iodopyridin-3-ol (2.55 g, 22.0 mmol) anddiisopropylethylamine (1.29 g, 10.0 mmol) were heated and stirred indimethylformamide (5 ml) at 130° C. for 3 hours. The reaction solutionwas distributed between an ethyl acetate-tetrahydrofuran mixed solventand water, the organic layer was washed with water and saturated brineand dried over anhydrous magnesium sulfate, the drying agent wasfiltered off and the filtrate was distilled off under reduced pressure.The obtained crude product was subjected to silica gel columnchromatography (eluent—ethyl acetate:hexane=3:1), and the fractioncontaining the target substance was concentrated, suspended in ethylacetate and diluted with hexane, after which the crystals were filteredout, washed with hexane and then blow-dried to obtain the title compound(2.16 g, 4.88 mmol, 49%) as colorless crystals.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 4.05 (3H, s), 4.06 (3H, s), 6.39 (1H,d, J=5.2 Hz), 7.20 (1H, d, J=8.2 Hz), 7.45 (1H, s), 7.48 (1H, s), 7.75(1H, d, J=8.2 Hz), 8.55 (1H, d, J=5.2 Hz).

Production Example 222-36-Chloro-5-(6,7-dimethoxyquinolin-4-yloxy)pyridin-2-ylamine

Benzophenoneimine (1.67 g, 9.21 mmol) and tert-butoxysodium (885 mg,9.21 mmol) were heated and stirred in toluene (40 ml) for 1 hour at 80°C. under a nitrogen atmosphere, and then4-(2-chloro-6-iodopyridin-3-yloxy)-6,7-dimethoxyquinoline (3.72 g, 8.40mmol), tris(dibenzylideneacetone)dipalladium(0) (86.9 mg, 0.084 mmol)and rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (157 mg, 0.252 mmol)were added and the mixture was heated and stirred at 90° C. for 6 hours.After completion of the reaction, the reaction mixture was filtered withcelite, the filtrate was subjected to silica gel column chromatography(eluent—ethyl acetate:hexane=3:1), and the fraction containing thetarget substance was concentrated to obtain a yellow oil (1.98 g). Theyellow oil (1.98 g) was dissolved in ethanol (20 ml), 1N aqueoushydrochloric acid (5 ml) was added and the mixture was stirred at roomtemperature for 1 hour. After completion of the reaction, the reactionsolution was neutralized with 5N aqueous sodium hydroxide (1 ml) anddistributed between ethyl acetate and water, the organic layer waswashed with water and saturated brine and dried over anhydrous magnesiumsulfate, the drying agent was filtered off and the filtrate wasdistilled off under reduced pressure. The obtained crude product wassubjected to silica gel column chromatography (eluent—ethyl acetate),and the fraction containing the target substance was concentrated toobtain the title compound (506 mg, 1.53 mmol, 18%) as colorlesscrystals.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 4.06 (3H, s), 4.07 (3H, s), 4.71 (2H,s), 6.34 (1H, d, J=5.2 Hz), 6.53 (1H, d, J=8.8 Hz), 7.37 (1H, d, J=8.8Hz), 7.43 (1H, s), 7.59 (1H, s), 8.50 (1H, d, J=5.2 Hz).

Production Example 222-45-(6,7-Dimethoxyquinolin-4-yloxy)pyridin-2-ylamine

After suspending6-chloro-5-(6,7-dimethoxyquinolin-4-yloxy)pyridin-2-ylamine (500 mg,1.51 mmol) in a mixed solvent of methanol (20 ml), tetrahydrofuran (10ml) and triethylamine (3 ml), palladium carbon (300 mg) was added andthe mixture was stirred for 15 hours at room temperature under ahydrogen atmosphere. The catalyst was filtered off by celite filtration,washing was performed with ethanol, and the filtrate was distilled offunder reduced pressure. The obtained crude product was subjected tosilica gel column chromatography (eluent—ethyl acetate), and thefraction containing the target substance was concentrated, suspended inethyl acetate and diluted with hexane, after which the crystals werefiltered out, washed with hexane and then blow-dried to obtain the titlecompound (138 mg, 0.465 mmol, 31%) as colorless crystals.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 4.05 (3H, s), 4.07 (3H, s), 4.52 (2H,s), 6.42 (1H, d, J=5.2 Hz), 6.61 (1H, d, J=8.8 Hz), 7.32 (1H, dd, J=2.8,8.8 Hz), 7.42 (1H, s), 7.57 (1H, s), 8.04 (1H, d, J=2.8 Hz), 8.49 (1H,d, J=5.2 Hz).

Example 223N-(5-(6,7-Dimethoxyquinolin-4-yloxy)pyridin-2-yl)-N′-(4-fluorophenyl)urea

The title compound (50.9 mg, 117 mmol, 78%) was obtained as colorlesscrystals from the 5-(6,7-dimethoxyquinolin-4-yloxy)pyridin-2-ylamine(44.5 mg, 0.150 mmol) obtained in Production Example 222-4 and4-fluorophenyl isocyanate (22.6 mg, 0.165 mmol), in the same manner asExample 222.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.94 (3H, s), 3.95 (3H, s), 6.53 (1H,d, J=5.2 Hz), 7.13-7.20 (2H, m), 7.41 (1H, s), 7.51-7.57 (3H, m),7.74-7.82 (2H, m), 8.30-8.33 (1H, m), 8.49 (1H, d, J=5.2 Hz), 9.55 (1H,s), 10.09 (1H, s).

Example 224N-(5-(6,7-Dimethoxyquinolin-4-yloxy)pyridin-2-yl)-N′-(thiazol-2-yl)urea

The 5-(6,7-dimethoxyquinolin-4-yloxy)pyridin-2-ylamine (44.5 mg, 0.150mmol) obtained in Production Example 222-4 and thiazol-2-ylcarbamic acidphenyl ester (39.6 mg, 0.180 mmol) were stirred in dimethylsulfoxide (1ml) at 85° C. for 2 hours. The reaction solution was distributed betweenethyl acetate and water, the organic layer was washed with water andsaturated brine and dried over anhydrous magnesium sulfate, the dryingagent was filtered off and the filtrate was distilled off under reducedpressure. The obtained crude product was subjected to silica gel columnchromatography (eluent—ethyl acetate:methanol=30:1), and the fractioncontaining the target substance was concentrated, suspended in ethylacetate and diluted with hexane, after which the crystals were filteredout, washed with hexane and then blow-dried to obtain the title compound(46.7 mg, 0.110 mmol, 74%) as colorless crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.95 (3H, s), 3.96 (3H, s), 6.53 (1H,d, J=5.2 Hz), 7.20 (1H, d, J=3.4 Hz), 7.41 (1H, s), 7.43 (1H, d, J=3.4Hz), 7.54 (1H, s), 7.80-7.86 (2H, m), 8.36-8.39 (1H, m), 8.49 (1H, d,J=5.2 Hz), 9.92 (1H, br s), 11.55 (1H, br s).

The intermediates were synthesized in the following manner.

Production Example 224-1 Thiazol-2-ylcarbamic acid phenyl ester

After dissolving 2-aminothiazole (5.01 g, 50.0 mmol) and pyridine (7.91g, 100 mmol) in dimethylformamide (50 ml), phenyl chloroformate (8.22 g,52.5 mmol) was added while cooling on ice, and the mixture was stirredat room temperature for 1 hour. The reaction solution was distributedbetween an ethyl acetate-tetrahydrofuran mixed solvent and water, theorganic layer was washed with water and saturated brine and dried overanhydrous magnesium sulfate, the drying agent was filtered off and thefiltrate was distilled off under reduced pressure. After adding ethylacetate and then hexane to the obtained crude product, the precipitatedcrystals were filtered out and blow-dried to obtain the title compound(10.6 g, 48.1 mmol, 96%) as colorless crystals.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 6.97 (1H, d, J=3.4 Hz), 7.24-7.32 (3H,m), 7.40-7.46 (2H, m), 7.52 (1H, d, J=3.4 Hz), 13.19 (1H, s).

Example 225N-(6-Chloro-5-(6,7-dimethoxyquinolin-4-yloxy)pyridin-2-yl)-N′-phenylurea

The 6-chloro-5-(6,7-dimethoxyquinolin-4-yloxy)pyridin-2-ylamine (33.2mg, 0.100 mmol) obtained in Production Example 222-3 and phenylisocyanate (13.1 mg, 0.110 mmol) were heated and stirred indimethylformamide (1 ml) at 60° C. for 2 hours. the reaction solutionwas distributed between ethyl acetate and water, the organic layer waswashed with water and saturated brine and dried over anhydrous magnesiumsulfate, the drying agent was filtered off and the filtrate wasdistilled off under reduced pressure. The obtained crude product wassubjected to silica gel column chromatography (eluent—ethyl acetate),and the fraction containing the target substance was concentrated,suspended in ethyl acetate and diluted with hexane, after which thecrystals were filtered out, washed with hexane and then blow-dried toobtain the title compound (17.5 mg, 0.039 mmol, 39%) as colorlesscrystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.96 (6H, s), 6.50 (1H, d, J=5.2 Hz),7.01-7.07 (1H, m), 7.30-7.37 (2H, m), 7.43 (1H, s), 7.46-7.51 (2H, m),7.54 (1H, s), 7.94-8.00 (2H, m), 8.49 (1H, d, J=5.2 Hz), 9.29 (1H, brs), 9.75 (1H, br s).

Example 226N-(5-(6,7-Dimethoxyquinolin-4-ylsulfanyl)thiophen-2-yl)-N′-phenylurea

5-(6,7-Dimethoxyquinolin-4-ylsulfanyl)thiophen-2-ylamine (89.0 mg, 0.280mmol) and phenyl isocyanate (36.6 mg, 0.307 mmol) were stirred indimethylformamide (1 ml) at room temperature for 1 hour. The reactionsolution was distributed between ethyl acetate and water, the organiclayer was washed with water and saturated brine and dried over anhydrousmagnesium sulfate, the drying agent was filtered off and the filtratewas distilled off under reduced pressure. The obtained crude product wassubjected to silica gel column chromatography (eluent—ethylacetate:methanol=50:1), and the fraction containing the target substancewas concentrated, suspended in ethyl acetate and diluted with hexane,after which the crystals were filtered out, washed with hexane and thenblow-dried to obtain the title compound (60.0 mg, 0.137 mmol, 48%) ascolorless crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.95 (3H, s), 3.98 (3H, s), 6.70 (1H,d, J=3.6 Hz), 6.74 (1H, d, J=4.8 Hz), 6.98-7.03 (1H, m), 7.26-7.36 (4H,m), 7.40 (1H, s), 7.43-7.50 (2H, m), 8.48 (1H, d, J=4.8 Hz), 9.02 (1H,br s), 10.27 (1H, br s).

The intermediates were synthesized in the following manner.

Production Example 226-1 6,7-Dimethoxy-1H-quinolin-4-thione

After suspending the 6,7-dimethoxy-1H-quinolin-4-one (10.3 g, 50.0 mmol)described in WO9717329, phosphorus pentasulfide (26.7 g, 60.0 mmol) andsodium bicarbonate (26.7 g, 318 mmol) in diglyme (diethyleneglycoldimethyl ether) (100 ml), the suspension was heated and stirred at 80°C. for 2 hours. The reaction solution was returned to room temperatureand poured into ice water (1000 ml), and the precipitated crystals werefiltered out, washed with water and blow-dried to obtain the titlecompound (8.19 g, 37.0 mmol, 74%) as yellow crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.87 (3H, s), 3.91 (3H, s), 7.07 (1H,s), 7.19 (1H, d, J=6.8 Hz), 7.74 (1H, d,

J=6.8 Hz), 8.11 (1H, s), 12.76 (1H, br s).

Production Example 226-26,7-Dimethoxy-4-(5-nitrothiophen-2-ylsulfanyl)quinoline

6,7-Dimethoxy-1H-quinolin-4-thione (2.21 g, 10.0 mmol),2-bromo-5-nitrothiophene (2.29 g, 11.0 mmol) and potassium carbonate(2.07 g, 15.0 mmol) were stirred in dimethylformamide (30 ml) at roomtemperature for 1 hour. The reaction solution was distributed betweenethyl acetate and water, the organic layer was washed with 1N aqueoussodium hydroxide, water and saturated brine and dried over anhydrousmagnesium sulfate, the drying agent was filtered off and the filtratewas distilled off under reduced pressure. The obtained crude product wassubjected to silica gel column chromatography (eluent—ethylacetate:hexane=3:1), and the fraction containing the target substancewas concentrated to obtain the title compound (1.93 g, 5.54 mmol, 55%)as yellow crystals.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 4.04 (3H, s), 4.06 (3H, s), 7.10 (1H,d, J=4.8 Hz), 7.22 (1H, d, J=4.4 Hz), 7.37 (1H, s), 7.46 (1H, s), 7.89(1H, d, J=4.4 Hz), 8.60 (1H, d, J=4.8 Hz).

Production Example 226-35-(6,7-Dimethoxyquinolin-4-ylsulfanyl)thiophen-2-ylamine

After suspending 6,7-dimethoxy-4-(5-nitrothiophen-2-ylsulfanyl)quinoline(1.39 g, 4.00 mmol), iron (1.12 g, 20.0 mmol) and ammonium chloride(2.18 g, 40.0 mmol) in an ethanol (32 ml)-water (8 ml) mixed solvent,the suspension was heated and stirred at 80° C. for 5 minutes. Aftercompletion of the reaction, the reaction mixture was filtered withcelite and washed in ethyl acetate. The organic layer was washed withwater and saturated brine and dried over anhydrous magnesium sulfate,the drying agent was filtered off and the filtrate was distilled offunder reduced pressure. The obtained crude product was subjected tosilica gel column chromatography (eluent—ethyl acetate:hexane=3:1), andthe fraction containing the target substance was concentrated to obtainthe title compound (1.93 g, 5.54 mmol, 55%) as yellowish-brown crystals.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 4.04 (3H, s), 4.06 (3H, s), 4.15 (2H,s), 6.21 (1H, d, J=3.8 Hz), 6.87 (1H, d, J=5.0 Hz), 7.04 (1H, d, J=3.8Hz), 7.31 (1H, s), 7.40 (1H, s), 8.47 (1H, d, J=5.0 Hz).

Example 227N-(5-(6,7-Dimethoxyquinolin-4-ylsulfanyl)thiophen-2-yl)-N′-(4-fluorophenyl)urea

The title compound (29.3 mg, 64.3 mmol, 64%) was obtained as colorlesscrystals from 5-(6,7-dimethoxyquinolin-4-ylsulfanyl)thiophen-2-ylamine(31.8 mg, 0.100 mmol) and 4-fluorophenyl isocyanate (15.1 mg, 0.110mmol), by the same procedure as in Example 226.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.94 (3H, s), 3.97 (3H, s), 6.70 (1H,d, J=4.0 Hz), 6.74 (1H, d, J=5.2 Hz), 7.10-7.18 (2H, m), 7.31 (1H, s),7.33 (1H, d, J=4.0 Hz), 7.39 (1H, s), 7.45-7.51 (2H, m), 8.48 (1H, d,J=5.2 Hz), 9.05 (1H, br s), 10.29 (1H, br s).

Example 228N-(5-(6,7-Dimethoxyquinolin-4-ylsulfanyl)thiophen-2-yl)-N′-(3-fluorophenyl)urea

The title compound (62.0 mg, 0.136 mmol, 68%) was obtained as lightbrown crystals from5-(6,7-dimethoxyquinolin-4-ylsulfanyl)thiophen-2-ylamine (64.0 mg, 0.200mmol) and 4-fluorophenyl isocyanate (15.1 mg, 0.110 mmol), by the sameprocedure as in Example 226.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.95 (3H, s), 3.97 (3H, s), 6.72 (1H,d, J=3.6 Hz), 6.75 (1H, d, J=4.6 Hz), 6.80-6.85 (1H, m), 7.17-7.21 (1H,m), 7.29-7.36 (3H, m), 7.40 (1H, s), 7.42-7.48 (1H, m), 8.48 (1H, d,J=4.6 Hz), 9.18 (1H, br s), 10.27 (1H, br s).

Example 229N-(3-Cyanophenyl)-N′-(5-(6,7-dimethoxyquinolin-4-ylsulfanyl)thiophen-2-yl)urea

The title compound (60.0 mg, 0.130 mmol, 65%) was obtained as lightbrown crystals from5-(6,7-dimethoxyquinolin-4-ylsulfanyl)thiophen-2-ylamine (64 mg, 0.200mmol) and 3-cyanophenyl isocyanate (31.7 mg, 0.220 mmol), by the sameprocedure as in Example 226.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.95 (3H, s), 3.97 (3H, s), 6.73-6.77(2H, m), 7.31 (1H, s), 7.34 (1H, d, J=4.0 Hz), 7.40 (1H, s), 7.44-7.48(1H, m), 7.49-7.54 (1H, m), 7.71-7.75 (1H, m), 7.94-7.96 (1H, m), 8.48(1H, d, J=4.8 Hz), 9.30 (1H, br s), 10.40 (1H, br s).

Example 230N-(5-(6,7-Dimethoxyquinolin-4-ylsulfanyl)thiophen-2-yl)-N′-(thiazol-2-yl)urea

5-(6,7-Dimethoxyquinolin-4-ylsulfanyl)thiophen-2-ylamine (31.8 mg, 0.100mmol) and thiazol-2-ylcarbamic acid phenyl ester (33.0 mg, 0.150 mmol)were stirred in dimethylsulfoxide (1 ml) at 85° C. for 2 hours. Thereaction solution was distributed between ethyl acetate and water, theorganic layer was washed with water and saturated brine and dried overanhydrous magnesium sulfate, the drying agent was filtered off and thefiltrate was distilled off under reduced pressure. The obtained crudeproduct was subjected to silica gel column chromatography (eluent—ethylacetate:methanol=20:1), and the fraction containing the target substancewas concentrated, suspended in ethyl acetate and diluted with hexane,after which the crystals were filtered out, washed with hexane and thenblow-dried to obtain the title compound (25.6 mg, 0.058 mmol, 58%) ascolorless crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.95 (3H, s), 3.97 (3H, s), 6.74 (1H,d, J=5.0 Hz), 6.75-6.80 (1H, m), 7.04-7.10 (1H, m), 7.32 (1H, s), 7.34(1H, d, J=4.0 Hz), 7.36-7.39 (1H, m), 7.40 (1H, s), 8.48 (1H, d, J=5.0Hz).

Example 231N-(5-(6,7-Dimethoxyquinolin-4-ylsulfanyl)thiophen-2-yl)-N′-(3-methanesulfonylphenyl)urea

The title compound (61.0 mg, 0.118 mmol, 59%) was obtained as lightbrown crystals from5-(6,7-dimethoxyquinolin-4-ylsulfanyl)thiophen-2-ylamine (64.0 mg, 0.200mmol) and (3-methanesulfonylphenyl)carbamic acid phenyl ester (87.4 mg,0.300 mmol), by the same procedure as in Example 230.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.20 (3H, s), 3.95 (3H, s), 3.97 (3H,s), 6.75 (1H, d, J=4.8 Hz), 6.76 (1H, d, J=4.0 Hz), 7.32 (1H, s), 7.35(1H, d, J=4.0 Hz), 7.40 (1H, s), 7.53-7.60 (2H, m), 7.70-7.74 (1H, m),8.13-8.16 (1H, m), 8.48 (1H, d, J=4.8 Hz), 9.40 (1H, br s), 10.35 (1H,br s).

Example 232N-(5-(6,7-Dimethoxyquinolin-4-ylsulfanyl)thiophen-2-yl)-N′-(2-hydroxymethylphenyl)urea

The title compound (27.0 mg, 0.058 mmol, 58%) was obtained as colorlesscrystals from(5-(6,7-dimethoxyquinolin-4-ylsulfanyl)thiophen-2-yl)carbamic acidphenyl ester (43.9 mg, 0.100 mmol) and 2-aminobenzyl alcohol (24.6 mg,0.200 mmol), by the same procedure as in Example 230.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.94 (3H, s), 3.96 (3H, s), 4.54 (2H,d, J=5.6 Hz), 5.51 (1H, t, J=5.6 Hz), 6.65 (1H, d, J=4.0 Hz), 6.74 (1H,d, J=4.8 Hz), 7.02-7.07 (1H, m), 7.22-7.27 (1H, m), 7.28-7.34 (3H, m),7.39 (1H, s), 7.80-7.84 (1H, m), 8.46-8.50 (2H, m), 10.89 (1H, br s).

The intermediates were synthesized in the following manner.

Production Example 232-1(5-(6,7-Dimethoxyquinolin-4-ylsulfanyl)thiophen-2-yl)carbamic acidphenyl ester

After dissolving5-(6,7-dimethoxyquinolin-4-ylsulfanyl)thiophen-2-ylamine (696 mg, 2.00mmol) and pyridine (174 mg, 2.20 mmol) in a tetrahydrofuran (10ml)-dimethylformamide (5 ml) mixed solvent, phenyl chloroformate (329mg, 2.10 mmol) was added while cooling on ice, and the mixture wasstirred at room temperature for 1 hour. The reaction solution wasdistributed between ethyl acetate and water, the organic layer waswashed with water and saturated brine and dried over anhydrous magnesiumsulfate, the drying agent was filtered off and the filtrate wasdistilled off under reduced pressure. After adding ethyl acetate andthen hexane to the obtained crude product, the precipitated crystalswere filtered out and blow-dried to obtain the title compound (720 mg,1.64 mmol, 82%) as yellowish-brown crystals.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 4.08 (3H, s), 4.09 (3H, s), 6.86-6.92(2H, m), 7.10-7.16 (2H, m), 7.20-7.26 (2H, m), 7.34 (1H, s), 7.36-7.41(2H, m), 7.80-7.85 (1H, m), 8.35 (1H, d, J=5.6 Hz), 8.75 (1H, br s).

Example 233N-(5-(6,7-Dimethoxyquinolin-4-ylsulfanyl)thiophen-2-yl)-N′-(3-hydroxymethylphenyl)urea

The title compound (25.0 mg, 0.054 mmol, 54%) was obtained as lightbrown crystals from the(5-(6,7-dimethoxyquinolin-4-ylsulfanyl)thiophen-2-yl)carbamic acidphenyl ester (43.9 mg, 0.100 mmol) obtained in Production Example 232-1and 3-aminobenzyl alcohol (24.6 mg, 0.200 mmol), by the same procedureas in Example 230.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.95 (3H, s), 3.97 (3H, s), 4.46 (2H,d, J=5.6 Hz), 5.19 (1H, t, J=5.6 Hz), 6.70 (1H, d, J=4.0 Hz), 6.75 (1H,d, J=4.8 Hz), 6.93-6.97 (1H, m), 7.21-7.26 (1H, m), 7.30-7.34 (3H, m),7.40 (1H, s), 7.43-7.46 (1H, m), 8.48 (1H, d, J=4.8 Hz), 8.97 (1H, s).

Example 234N-(5-(6,7-Dimethoxyquinolin-4-ylsulfanyl)thiophen-2-yl)-N′-(4-hydroxymethylphenyl)urea

The title compound (27.0 mg, 0.058 mmol, 58%) was obtained as lightyellow crystals from(5-(6,7-dimethoxyquinolin-4-ylsulfanyl)thiophen-2-yl)carbamic acidphenyl ester (43.9 mg, 0.100 mmol) and 4-aminobenzyl alcohol (224 mg,1.82 mmol), by the same procedure as in Example 230.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.94 (3H, s), 3.97 (3H, s), 4.42 (2H,d, J=5.6 Hz), 5.07 (1H, t, J=5.6 Hz), 6.69 (1H, d, J=4.0 Hz), 6.75 (1H,d, J=5.0 Hz), 7.21-7.26 (2H, m), 7.30-7.34 (2H, m), 7.38-7.43 (3H, m),8.47 (1H, d, J=5.0 Hz), 8.88 (1H, s), 10.13 (1H, s).

Example 235N-(2-(6,7-Dimethoxyquinolin-4-ylsulfanyl)thiazol-5-yl)-N′-phenylurea

2-(6,7-Dimethoxyquinolin-4-ylsulfanyl)thiazol-5-ylamine (64.0 mg, 0.200mmol) and phenyl isocyanate (26.2 mg, 0.220 mmol) were stirred indimethylformamide (1 ml) at room temperature for 15 hours. The reactionsolution was distributed between ethyl acetate and water, the organiclayer was washed with water and saturated brine and dried over anhydrousmagnesium sulfate, the drying agent was filtered off and the filtratewas distilled off under reduced pressure. The obtained crude product wassubjected to silica gel column chromatography (eluent—ethylacetate:methanol=30:1), and the fraction containing the target substancewas concentrated, suspended in ethyl acetate and diluted with hexane,after which the crystals were filtered out, washed with hexane and thenblow-dried to obtain the title compound (53.2 mg, 0.121 mmol, 60%) ascolorless crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.94 (3H, s), 3.95 (3H, s), 6.98-7.05(2H, m), 7.26-7.34 (2H, m), 7.39 (1H, s), 7.43-7.47 (3H, m), 7.64 (1H,s), 8.55 (1H, d, J=4.8 Hz), 9.10 (1H, s), 10.29 (1H, br s).

The intermediates were synthesized in the following manner.

Production Example 235-16,7-Dimethoxy-4-(5-nitrothiazol-2-ylsulfanyl)quinoline

After suspending 6,7-dimethoxy-1H-quinoline-4-thione (2.21 g, 10.0 mmol)in dimethylformamide (30 ml), 2-bromo-5-nitrothiazole (2.30 g, 11.0mmol) was added at 0° C., and then the mixture was stirred at roomtemperature for 1 hour. The reaction solution was distributed betweenethyl acetate and 1N aqueous sodium hydroxide, the organic layer waswashed with water and saturated brine and dried over anhydrous magnesiumsulfate, the drying agent was filtered off and the filtrate wasdistilled off under reduced pressure. The obtained crude product wassubjected to silica gel column chromatography (eluent—ethylacetate:hexane=3:1), and the fraction containing the target substancewas concentrated, suspended in ethyl acetate and diluted with hexane,after which the crystals were filtered out, washed with hexane and thenblow-dried to obtain the title compound (1.70 g, 4.87 mmol, 49%) aslight yellow crystals.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 4.00 (3H, s), 4.08 (3H, s), 7.50 (1H,s), 7.54 (1H, s), 7.70 (1H, d, J=4.8 Hz), 8.37 (1H, s), 8.83 (1H, d,J=4.8 Hz).

Production Example 235-22-(6,7-Dimethoxyquinolin-4-ylsulfanyl)thiazol-5-ylamine

After suspending 6,7-dimethoxy-4-(5-nitrothiazol-2-ylsulfanyl)quinoline(699 mg, 2.00 mmol), iron (559 mg, 10.0 mmol) and ammonium chloride(1.07 g, 20.0 mmol) in an ethanol (20 ml)-water (5 ml) mixed solvent,the suspension was heated and stirred at 80° C. for 20 minutes. Aftercompletion of the reaction, the reaction mixture was filtered withcelite and washed in an ethyl acetate-tetrahydrofuran mixed solvent. Theorganic layer was washed with water and saturated brine and dried overanhydrous magnesium sulfate, the drying agent was filtered off and thefiltrate was distilled off under reduced pressure. The obtained crudeproduct was subjected to silica gel column chromatography (eluent—ethylacetate:methanol=30:1), and the fraction containing the target substancewas concentrated to obtain the title compound (190 mg, 0.595 mmol, 30%)as yellowish-brown crystals.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 3.99 (2H, br s), 4.04 (3H, s), 4.05(3H, s), 7.10 (1H, d, J=5.2 Hz), 7.17 (1H, s), 7.41 (1H, s), 7.42 (1H,s), 8.54 (1H, d, J=5.2 Hz).

Example 236N-(2-(6,7-Dimethoxyquinolin-4-ylsulfanyl)thiazol-5-yl)-N′-(4-fluorophenyl)urea

The title compound (62.3 mg, 0.136 mmol, 68%) was obtained as colorlesscrystals from 2-(6,7-dimethoxyquinolin-4-ylsulfanyl)thiazol-5-ylamine(64.0 mg, 0.200 mmol) and 4-fluorophenyl isocyanate (30.1 mg, 0.220mmol), by the same procedure as in Example 235.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.94 (3H, s), 3.95 (3H, s), 7.03 (1H,d, J=4.8 Hz), 7.10-7.18 (2H, m), 7.39 (1H, s), 7.42-7.48 (3H, m), 7.64(1H, s), 8.55 (1H, d, J=4.8 Hz), 9.14 (1H, s), 10.32 (1H, br s).

Example 237N-(2-(6,7-Dimethoxyquinolin-4-ylsulfanyl)thiazol-5-yl)-N′-(3-fluorophenyl)urea

The title compound (70.0 mg, 0.153 mmol, 51%) was obtained as colorlesscrystals from 2-(6,7-dimethoxyquinolin-4-ylsulfanyl)thiazol-5-ylamine(95.8 mg, 0.300 mmol) and 3-fluorophenyl isocyanate (45.2 mg, 0.330mmol), by the same procedure as in Example 235.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.94 (3H, s), 3.95 (3H, s), 6.80-6.86(1H, m), 7.06 (1H, d, J=4.8 Hz), 7.16-7.20 (1H, m), 7.28-7.35 (1H, m),7.38-7.45 (3H, m), 7.66 (1H, s), 8.55 (1H, d, J=4.8 Hz), 9.33 (1H, s),10.37 (1H, br s).

Example 238N-(3-Cyanophenyl)-N′-(2-(6,7-dimethoxyquinolin-4-ylsulfanyl)thiazol-5-yl)urea

The title compound (94.0 mg, 0.203 mmol, 68%) was obtained as lightyellow crystals from2-(6,7-dimethoxyquinolin-4-ylsulfanyl)thiazol-5-ylamine (95.8 mg, 0.300mmol) and 3-cyanophenyl isocyanate (47.6 mg, 0.330 mmol), by the sameprocedure as in Example 235.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.94 (3H, s), 3.95 (3H, s), 7.07 (1H,d, J=4.8 Hz), 7.40 (1H, s), 7.43 (1H, s), 7.45-7.54 (2H, m), 7.67 (1H,s), 7.70-7.74 (1H, m), 7.91-7.94 (1H, m), 8.56 (1H, d, J=4.8 Hz), 9.44(1H, s), 10.49 (1H, br s).

Example 239N-(2,4-Difluorophenyl)-N′-(2-(6,7-dimethoxyquinolin-4-ylsulfanyl)thiazol-5-yl)urea

The title compound (123 mg, 0.259 mmol, 86%) was obtained as lightorange crystals from2-(6,7-dimethoxyquinolin-4-ylsulfanyl)thiazol-5-ylamine (95.8 mg, 0.300mmol) and 2,4-difluorophenyl isocyanate (51.2 mg, 0.330 mmol), by thesame procedure as in Example 235.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.94 (3H, s), 3.95 (3H, s), 7.04 (1H,d, J=4.8 Hz), 7.05-7.09 (1H, m), 7.30-7.37 (1H, m), 7.39 (1H, s), 7.43(1H, s), 7.65 (1H, s), 7.84-7.91 (1H, m), 8.54 (1H, d, J=4.8 Hz), 8.84(1H, s), 10.48 (1H, br s).

Example 240N-(2-Chlorophenyl)-N′-(2-(6,7-dimethoxyquinolin-4-ylsulfanyl)thiazol-5-yl)urea

The title compound (132 mg, 0.279 mmol, 93%) was obtained as light browncrystals from 2-(6,7-dimethoxyquinolin-4-ylsulfanyl)thiazol-5-ylamine(95.8 mg, 0.300 mmol) and 2-chlorophenyl isocyanate (50.6 mg, 0.330mmol), by the same procedure as in Example 235.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.94 (3H, s), 3.95 (3H, s), 7.05 (1H,d, J=5.0 Hz), 7.07-7.12 (1H, m), 7.28-7.34 (1H, m), 7.39 (1H, s), 7.43(1H, s), 7.47-7.50 (1H, m), 7.67 (1H, s), 8.01-8.04 (1H, m), 8.55 (1H,d, J=5.0 Hz), 8.62 (1H, s), 10.85 (1H, br s).

Example 241N-(3-Chlorophenyl)-N′-(2-(6,7-dimethoxyquinolin-4-ylsulfanyl)thiazol-5-yl)urea

The title compound (124 mg, 0.262 mmol, 87%) was obtained as light browncrystals from 2-(6,7-dimethoxyquinolin-4-ylsulfanyl)thiazol-5-ylamine(95.8 mg, 0.300 mmol) and 3-chlorophenyl isocyanate (50.6 mg, 0.330mmol), by the same procedure as in Example 235.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.94 (3H, s), 3.95 (3H, s), 7.04-7.09(2H, m), 7.30-7.34 (2H, m), 7.40 (1H, s), 7.43 (1H, s), 7.63-7.66 (2H,m), 8.55 (1H, d, J=4.8 Hz), 9.30 (1H, s), 10.40 (1H, br s).

Example 242N-(4-Chlorophenyl)-N′-(2-(6,7-dimethoxyquinolin-4-ylsulfanyl)thiazol-5-yl)urea

The title compound (120 mg, 0.253 mmol, 85%) was obtained as colorlesscrystals from 2-(6,7-dimethoxyquinolin-4-ylsulfanyl)thiazol-5-ylamine(95.8 mg, 0.300 mmol) and 4-chlorophenyl isocyanate (50.6 mg, 0.330mmol), by the same procedure as in Example 235.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.94 (3H, s), 3.95 (3H, s), 7.04 (1H,d, J=4.8 Hz), 7.31-7.36 (2H, m), 7.39 (1H, s), 7.43 (1H, s), 7.45-7.50(2H, m), 7.65 (1H, s), 8.55 (1H, d, J=4.8 Hz), 9.24 (1H, s), 10.34 (1H,br s).

Example 243N-(2-(6,7-Dimethoxyquinolin-4-ylsulfanyl)thiazol-5-yl)-N′-(thiazol-2-yl)urea

After dissolving 2-(6,7-dimethoxyquinolin-4-ylsulfanyl)thiazol-5-ylamine(216 mg, 0.676 mmol) and pyridine (58.8 mg, 0.743 mmol) intetrahydrofuran (3 ml), 4-nitrophenyl chloroformate (150 mg, 0.743 mmol)was added while cooling on ice, the mixture was stirred at roomtemperature for 30 minutes, 2-aminothiazole (101 mg, 1.01 mmol) andtriethylamine (1 ml) were added, and the mixture was heated and stirredat 60° C. for 1 hour. The reaction solution was distributed betweenethyl acetate and water, the organic layer was washed with water andsaturated brine and dried over anhydrous magnesium sulfate, the dryingagent was filtered off and the filtrate was distilled off under reducedpressure. The obtained crude product was subjected to silica gel columnchromatography (eluent—ethyl acetate:methanol=30:1), and the fractioncontaining the target substance was concentrated, suspended in ethylacetate and diluted with hexane, after which the crystals were filteredout, washed with hexane and then blow-dried to obtain the title compound(57 mg, 0.128 mmol, 19%) as colorless crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.94 (3H, s), 3.95 (3H, s), 7.03-7.09(2H, m), 7.34-7.38 (1H, m), 7.40 (1H, s), 7.43 (1H, s), 7.66 (1H, br s),8.55 (1H, d, J=4.8 Hz).

Example 2447-Methoxy-4-(5-(3-phenylureido)thiophen-2-ylsulfanyl)quinoline-6-carboxamide

4-(5-Aminothiophen-2-ylsulfanyl)-7-methoxyquinoline-6-carboxamide (49.0mg, 0.150 mmol) and phenyl isocyanate (19.6 mg, 0.165 mmol) were stirredin dimethylformamide (1 ml) at room temperature for 2 hours. Thereaction solution was distributed between ethyl acetate and water, theorganic layer was washed with water and saturated brine and dried overanhydrous magnesium sulfate, the drying agent was filtered off and thefiltrate was distilled off under reduced pressure. The obtained crudeproduct was suspended in ethyl acetate and diluted with hexane, and thenthe crystals were filtered out, washed with hexane and blow-dried toobtain the title compound (25.0 mg, 0.056 mmol, 37%) as light yellowcrystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 4.02 (3H, s), 6.72 (1H, d, J=3.4 Hz),6.77 (1H, d, J=4.8 Hz), 6.98-7.03 (1H, m), 7.27-7.34 (2H, m), 7.35 (1H,d, J=3.4 Hz), 7.43-7.49 (2H, m), 7.53 (1H, s), 7.80 (1H, br s), 7.89(1H, br s), 8.52 (1H, s), 8.65 (1H, d, J=4.8 Hz), 8.95 (1H, br s), 10.21(1H, br s).

The intermediates were synthesized in the following manner.

Production Example 244-17-Methoxy-4-(5-nitrothiophen-2-ylsulfanyl)quinoline-6-carboxamide

4-Chloro-7-methoxyquinoline-6-carboxamide (1.18 g, 5.00 mmol) and sodiumsulfide (1.20 g, 5.50 mmol) were heated and stirred in dimethylformamide(10 ml) at 60° C. for 3 hours. After cooling the reaction solution toroom temperature, 2-bromo-5-nitrothiophene (1.25 g, 6.00 mmol) was addedand the mixture was further heated and stirred at 60° C. for 1 hour. Thereaction solution was returned to room temperature and then poured intoice water (50 ml), and the precipitated crystals were filtered out,washed with water and methanol and then blow-dried to obtain the titlecompound (700 mg, 1.94 mmol, 39%) as yellowish-brown crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 4.04 (3H, s), 7.17 (1H, d, J=4.6 Hz),7.59 (1H, s), 7.66 (1H, d, J=4.0 Hz), 7.82 (1H, br s), 7.90 (1H, br s),8.23 (1H, d, J=4.0 Hz), 8.53 (1H, s), 8.76 (1H, d, J=4.6 Hz).

Production Example 244-2(4-(5-Aminothiophen-2-ylsulfanyl)-7-methoxyquinoline-6-carboxamide)

After suspending7-methoxy-4-(5-nitrothiophen-2-ylsulfanyl)quinoline-6-carboxamide (320mg, 0.885 mmol), iron (247 mg, 4.43 mmol) and ammonium chloride (481 mg,8.85 mmol) in an ethanol (8 ml)-water (2 ml)-dimethylformamide (1 ml)mixed solvent, the suspension was heated and stirred at 80° C. for 15minutes. After completion of the reaction, the reaction mixture wasfiltered with celite and washed in a tetrahydrofuran-methanol mixedsolvent. After adding ethyl acetate to the organic layer, it was washedwith water and saturated brine and dried over anhydrous magnesiumsulfate, the drying agent was filtered off and the filtrate wasdistilled off under reduced pressure. The obtained crude product wassubjected to silica gel column chromatography (eluent—ethylacetate:methanol=20:1), and the fraction containing the target substancewas concentrated to obtain the title compound (164 mg, 0.495 mmol, 56%)as yellowish-brown crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 4.02 (3H, s), 6.00 (1H, d, J=4.0 Hz),6.34 (2H, s), 6.83 (1H, d, J=4.8 Hz), 7.08 (1H, d, J=4.0 Hz), 7.51 (1H,s), 7.77 (1H, br s), 7.86 (1H, br s), 8.47 (1H, s), 8.66 (1H, d, J=4.8Hz).

Example 2454-(5-(3-(4-Fluorophenyl)ureido)thiophen-2-ylsulfanyl)-7-methoxyquinoline-6-carboxamide

The title compound (50.0 mg, 0.107 mmol, 71%) was obtained as colorlesscrystals from4-(5-aminothiophen-2-ylsulfanyl)-7-methoxyquinoline-6-carboxamide (49.0mg, 0.150 mmol) and 4-fluorophenyl isocyanate (22.6 mg, 0.165 mmol), bythe same procedure as in Example 244.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 4.03 (3H, s), 6.72 (1H, d, J=4.0 Hz),6.76 (1H, d, J=4.8 Hz), 7.10-7.18 (2H, m), 7.35 (1H, d, J=4.0 Hz),7.45-7.51 (2H, m), 7.53 (1H, s), 7.80 (1H, br s), 7.89 (1H, br s), 8.52(1H, s), 8.65 (1H, d, J=4.8 Hz), 8.99 (1H, br s), 10.24 (1H, br s).

Example 2467-Methoxy-4-(5-(3-thiazol-2-ylureido)thiophen-2-ylsulfanyl)quinoline-6-carboxamide

4-(5-Aminothiophen-2-ylsulfanyl)-7-methoxyquinoline-6-carboxamide (66.0mg, 0.200 mmol) and thiazol-2-ylcarbamic acid phenyl ester (66.0 mg,0.300 mmol) were stirred in dimethylsulfoxide (1 ml) at 85° C. for 2hours. The reaction solution was distributed between ethyl acetate andwater, the organic layer was washed with water and saturated brine anddried over anhydrous magnesium sulfate, the drying agent was filteredoff and the filtrate was distilled off under reduced pressure. Theobtained crude product was subjected to silica gel column chromatography(eluent—ethyl acetate:methanol=15:1), and the fraction containing thetarget substance was concentrated, suspended in ethyl acetate anddiluted with hexane, after which the crystals were filtered out, washedwith hexane and then blow-dried to obtain the title compound (35.0 mg,0.077 mmol, 38%) as colorless crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 4.03 (3H, s), 6.77 (1H, d, J=4.8 Hz),6.77-6.83 (1H, m), 7.01-7.12 (1H, m), 7.34-7.39 (2H, m), 7.51 (1H, s),7.80 (1H, br s), 7.89 (1H, br s), 8.52 (1H, s), 8.65 (1H, d, J=4.8 Hz).

Example 247N1-[5-({7-[3-(Dimethylamino)propoxy]-6-methoxy-4-quinolyl}sulfanyl)-2-thienyl]-N′-(4-fluorophenyl)urea

5-({7-[3-(Dimethylamino)propoxy]-6-methoxy-4-quinolyl}sulfanyl)-2-thiophenylamine(190 mg), para-fluorophenyl isocyanate (69 mg) and tetrahydrofuran (30ml) were stirred together at room temperature for 30 minutes. Theorganic solvent was distilled off under reduced pressure, and theresidue was purified by column chromatography (ethyl acetate, followedby ethyl acetate:methanol=10:1) using NH type silica gel. The solventwas distilled off under reduced pressure, and ethyl acetate was added tothe residue for solidification to obtain 16 mg of a yellowish-brownsolid.

¹H-NMR (DMSO-d₆) δ (ppm): 0.93 (6H, t, J=7.2 Hz), 1.87 (2H, tt, J=7.2Hz, 7.2 Hz), 2.40-2.57 (6H, m), 3.94 (3H, s), 4.15 (2H, t, J=7.2 Hz),6.68 (1H, d, J=4.0 Hz), 6.71 (1H, d, J=4.8 Hz), 7.11 (2H, dd, J=8.8 Hz,8.8 Hz), 7.28 (1H, s), 7.30 (1H, d, J=4.0 Hz), 7.34 (1H, s), 7.45 (2H,dd, J=8.8 Hz, 4.8 Hz), 8.44 (1H, d, J=4.8 Hz), 8.94 (1H, bs), 10.15 (1H,bs).

The intermediates were obtained in the following manner.

Production Example 247-17-(Benzyloxy)-6-methoxy-1,4-dihydro-4-quinolinethione

7-(Benzyloxy)-6-methoxy-1,4-dihydro-4-quinoline (28.1 g), diphosphoruspentasulfide (53.4 g), sodium bicarbonate (53.7 g) and diethyleneglycoldimethyl ether (200 ml) were stirred together at 80° C. for 2 hours.After returning the mixture to room temperature, it was developed in icewater and stirred for 40 minutes, and then the solid was filtered outand blow-dried at 60° C. to obtain 29.1 g of a yellow powder.

¹H-NMR (DMSO-d₆) δ (ppm): 3.85 (3H, s), 5.22 (2H, s), 7.15 (1H, s), 7.17(1H, d, J=6.4 Hz), 7.33-7.50 (5H, m), 7.71 (1H, d, J=6.4 Hz), 8.11 (1H,s).

Production Example 247-22-{[7-(Benzyloxy)-6-methoxy-4-quinolyl]sulfanyl}-5-nitrothiophene

7-(Benzyloxy)-6-methoxy-1,4-dihydro-4-quinolinethione (14.3 g),2-bromo-5-nitrothiophene (10 g), potassium carbonate (9.9 g) anddimethylformamide (150 ml) were stirred together at room temperature for6 hours. Water was added, and the precipitated solid was filtered outand washed with water and then ethyl acetate to obtain 15.7 g of ayellow powder.

¹H-NMR (DMSO-d₆) δ (ppm): 3.92 (3H, s), 5.29 (2H, s), 7.23 (1H, dd,J=4.8 Hz, 1.6 Hz), 7.32-7.44 (4H, m), 7.49 (2H, d, J=8.0 Hz), 7.55 (1H,s), 7.57 (1H, dd, J=4.4 Hz, 1.6 Hz), 8.16 (1H, dd, J=4.4 Hz, 2.0 Hz),8.58 (1H, dd, J=4.8 Hz, 1.6 Hz).

Production Example 247-36-Methoxy-4-[(5-nitro-2-thienyl)sulfanyl]-7-quinolinol

7-(Benzyloxy)-6-methoxy-4-[(5-nitro-2-thienyl)sulfanyl]quinoline (4.0g), trifluoroacetic acid (40 ml) and thioanisole (4 ml) were stirredtogether at 65° C. for 2 hours. The mixture was returned to roomtemperature, the solvent was distilled off under reduced pressure, 80 mlof methanol was added to the residue, and then sodium bicarbonate waterwas added until the foaming subsided. The precipitated solid wasfiltered out to obtain 2.7 g of a yellow powder.

¹H-NMR (DMSO-d₆) δ (ppm): 3.92 (3H, s), 7.16 (1H, d, J=4.8 Hz), 7.31(1H, s), 7.33 (1H, s), 7.55 (1H, d, J=4.0 Hz), 8.15 (1H, d, J=4.0 Hz),8.52 (1H, d, J=4.8 Hz).

Production Example 247-4N,N-Diethyl-N-[3-({6-methoxy-4-[(5-nitro-2-thienyl)sulfanyl]-7-quinolyl}oxy)propyl]amine

6-Methoxy-4-[(5-nitro-2-thienyl)sulfanyl]-7-quinolinol (500 mg),3-diethylaminopropanol (290 mg), diethyl azodicarboxylate (390 mg),triphenylphosphine (590 mg), tetrahydrofuran (30 ml),1-methyl-2-pyrrolidinone (2 ml) and dimethylsulfoxide (10 ml) werestirred together at 0° C. for 5 hours and then at room temperature for10 hours. Water was added, extraction was performed with ethyl acetate,and the extract was back extracted with 2N aqueous hydrochloric acid.After adding 5N aqueous sodium hydroxide to the hydrochloric acidextract and performing extraction with ethyl acetate, the extract waswashed with water and then with brine and dried over magnesium sulfate.NH type silica gel was coated onto a glass filter, the ethyl acetatelayer was passed through the filter, and the solvent was distilled offunder reduced pressure to obtain 500 mg of a reddish-brown oil.

¹H-NMR (DMSO-d₆) δ (ppm): 0.92 (6H, t, J=7.2 Hz), 1.87 (2H, tt, J=7.2Hz, 7.2 Hz), 2.40-2.58 (6H, m), 3.93 (3H, s), 4.20 (2H, t, J=7.2 Hz),7.21 (1H, d, J=4.8 Hz), 7.37 (1H, s), 7.42 (1H, s), 7.58 (1H, d, J=4.0Hz), 8.18 (1H, d, J=4.0 Hz), 8.60 (1H, d, J=4.8 Hz).

Production Example 247-55-({7-[3-(Diethylamino)propoxy]-6-methoxy-4-quinolyl}sulfanyl)-2-thiopheneamine

N,N-Diethyl-N-[3-({6-methoxy-4-[(5-nitro-2-thienyl)sulfanyl]-7-quinolyl}oxy)propyl]amine(525 mg), iron powder (330 mg), ammonium chloride (660 mg), ethanol (20ml) and water (5 ml) were stirred together at 80° C. for 80 minutes.After filtration with celite, NH type silica gel was added to thefiltrate, the solvent was distilled off under reduced pressure and thereaction product was adsorbed onto the silica gel. The silica gel wascharged into a dry column packed with NH type silica gel, and columnpurification was performed (ethyl acetate, followed by ethylacetate:methanol=3:1) to obtain 190 mg of a brown oil.

¹H-NMR (DMSO-d₆) δ (ppm): 0.91 (6H, t, J=7.2 Hz), 1.88 (2H, tt, J=7.2Hz, 7.2 Hz), 2.47-2.57 (6H, m), 3.92 (3H, s), 4.16 (2H, t, J=7.2 Hz),5.96 (1H, d, J=4.0 Hz), 6.76 (1H, d, J=4.8 Hz), 6.25-6.30 (2H, m), 7.04(1H, d, J=4.0 Hz), 7.22 (1H, s), 7.33 (1H, s), 8.45 (1H, d, J=4.8 Hz).

Example 248N-[2-({7-[3-(Diethylamino)propoxy]-6-methoxy-4-quinolyl}sulfanyl)-1,3-thiazol-5-yl]-N′-(4-fluorophenyl)urea

N,N-Diethyl-N-[3-({6-methoxy-4-[(5-nitro-1,3-thiazol-2-yl)sulfanyl]-7-quinolyl}oxy)propyl]amine(770 mg), iron powder (480 mg), ethanol (17 ml) and acetic acid (3.4 ml)were stirred together at 80° C. for 10 minutes. After adding 100 ml ofwater, 60 ml of ethyl acetate and 10 g of potassium carbonate to thereaction solution, the mixture was filtered through celite. The filtratewas subjected to liquid separation and ethyl acetate layer was passedthrough a glass filter coated with NH type silica gel. After adding 0.58ml of p-fluorophenyl isocyanate to the obtained ethyl acetate solution,the mixture was stirred at room temperature for 17 hours. NH type silicagel was added to the reaction solution, the solvent was distilled offunder reduced pressure and the reaction product was adsorbed onto thesilica gel. The silica gel was charged into a dry column packed with NHtype silica gel, and column purification was performed (ethylacetate:methanol=100:1, followed by 50:1, 10:1) to obtain 30 mg of thetarget substance as a light yellow solid.

¹H-NMR (DMSO-d₆) δ (ppm): 0.93 (6H, t, J=7.2 Hz), 1.88 (2H, tt, J=6.4Hz, 6.4 Hz), 2.46 (4H, q, J=7.2 Hz), 2.55 (2H, t, J=6.4 Hz), 3.92 (3H,s), 4.17 (2H, t, J=6.4 Hz), 7.00 (1H, d, J=5.2 Hz), 7.10 (2H, dd, J=8.8Hz, 8.8 Hz), 7.36 (1H, s), 7.38 (1H, s), 7.43 (2H, dd, J=8.8 Hz, 4.8Hz), 7.60 (1H, s), 8.51 (1H, d, J=5.2 Hz), 9.10 (1H. bs).

The intermediates were obtained in the following manner.

Production Example 248-12-{[7-(Benzyloxy)-6-methoxy-4-quinolyl]sulfanyl}-5-nitro-1,3-thiazole

7-(Benzyloxy)-6-methoxy-1,4-dihydro-4-quinolinethione (14.8 g),2-bromo-5-nitro-1,3-thiazole (10.4 g), potassium carbonate (10.3 g) anddimethylformamide (150 ml) were stirred together at room temperature for50 minutes. After adding 800 ml of water to the reaction solution, theprecipitated solid was filtered out and washed with ethyl acetate toobtain 13.4 g of a light ochre powder.

¹H-NMR (DMSO-d₆) δ (ppm): 3.87 (3H, s), 5.32 (2H, s), 7.32-7.53 (6H, m),7.64 (1H, s), 7.86 (1H, d, J=4.8 Hz), 8.70 (1H, s), 8.80 (1H, d, J=4.8Hz).

Production Example 248-26-Methoxy-4-[(5-nitro-1,3-thiazol-2-yl)sulfanyl]-7-quinolinol

2-{[7-(Benzyloxy)-6-methoxy-4-quinolyl]sulfanyl}-5-nitro-1,3-thiazole(2.0 g), trifluoroacetic acid (20 ml) and thioanisole (2 ml) werestirred together at 65° C. for 90 minutes. The mixture was returned toroom temperature, the solvent was distilled off under reduced pressure,40 ml of methanol was added to the residue, and then sodium bicarbonatewater was added until the foaming subsided. The precipitated solid wasfiltered out to obtain 1.4 g of a yellow powder.

¹H-NMR (DMSO-d₆) δ (ppm): 3.87 (3H, s), 7.40 (1H, s), 7.43 (1H, s), 7.78(1H, d, J=4.8 Hz), 8.71 (1H, d, J=2.4 Hz), 8.74 (1H, dd, J=4.8 Hz, 2.4Hz), 10.52 (1H, s).

Production Example 248-3N,N-Diethyl-N-[3-({6-methoxy-4-[(5-nitro-1,3-thiazol-2-yl)sulfanyl]-7-quinolyl}oxy)propyl]amine

The target substance was obtained using6-methoxy-4-[(5-nitro-1,3-thiazol-2-yl)sulfanyl]-7-quinolinol, in thesame manner as Production Example 247-2.

¹H-NMR (DMSO-d6) δ (ppm): 0.95 (6H, t, J=6.8 Hz), 1.91 (2H, tt, J=6.4Hz, 6.4 Hz), 2.45-2.65 (6H, m), 3.86 (3H, s), 4.20 (2H, t, J=6.4 Hz),7.42 (1H, s), 7.49 (1H, s), 7.83 (1H, d, J=4.4 Hz), 8.69 (1H, s), 8.79(1H, d, J=4.4 Hz).

Example 249N6-(2-Methoxyethyl)-4-(3-chloro-4-{[(cyclopropylamino)carbonyl]amino}phenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxamide

4-(3-Chloro-4-{[(cyclopropylamino)carbonyl]amino}phenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxylicacid (200 mg), 2-methoxyethylamine (38 mg),benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(Bop reagent) (230 mg), triethylamine (0.12 ml) and dimethylformamide (5ml) were stirred together at room temperature for 14 hours. Water andethyl acetate were added to the reaction solution for extraction, NHtype silica gel was added to the extract, the solvent was distilled offunder reduced pressure and the reaction product was adsorbed onto thesilica gel. The silica gel was charged into a dry column packed with NHtype silica gel, and column purification was performed (ethyl acetate).The solvent was distilled off under reduced pressure to obtain 120 mg ofthe target substance as a solid.

¹H-NMR (DMSO-d₆) δ (ppm): 0.38-0.45 (2H, m), 0.62-0.68 (2H, m),2.48-2.60 (1H, m), 3.30 (3H, s), 3.37 (3H, s), 3.45-3.55 (4H, m), 3.79(2H, t, J=4.4 Hz), 4.40 (2H, t, J=4.4 Hz), 6.52 (1H, d, J=5.2 Hz), 7.18(1H, d, J=2.8 Hz), 7.23 (1H, dd, J=9.2 Hz, 2.8 Hz), 7.49 (1H, d, J=2.8Hz), 7.55 (1H, s), 7.97 (1H, s), 8.26 (1H, d, J=9.2 Hz), 8.42-8.47 (1H,m), 8.66 (1H, d, J=5.2 Hz), 8.74 (1H, s).

The intermediates were obtained in the following manner.

Production Example 249-1 Methyl4-chloro-7-(2-methoxyethoxy)-6-quinolinecarboxylate

7-(2-Methoxyethoxy)-4-oxo-1,4-dihydro-6-quinoline carboxylic acid (7.5g), thionyl chloride (60 ml) and dimethylformamide (1 ml) were stirredtogether at 80° C. for 3 hours. The reaction solution was distilled offunder reduced pressure, toluene was added to the residue, anddistillation under reduced pressure was repeated twice. After addingmethanol to the residue, 10 ml of triethylamine was added. The resultingsolution was distilled off under reduced pressure and then water and 5Naqueous sodium hydroxide were added to pH 4 and extraction was performedwith ethyl acetate. The obtained ethyl acetate layer was passed througha glass filter coated with NH type silica gel, and then the solvent wasdistilled off under reduced pressure. Ether was added to the residue,and the solid was filtered out to obtain 3.6 g of the target substanceas a light brown solid. The filtrate was purified by columnchromatography (hexane:ethyl acetate=3:1) using NH type silica gel toobtain 1.3 g of the target substance as a light yellow solid.

¹H-NMR (DMSO-d₆) δ (ppm): 3.33 (3H, s), 3.71-3.75 (2H, m), 3.86 (3H, s),4.32-4.35 (2H, m), 7.62 (1H, s), 7.66 (1H, d, J=4.8 Hz), 8.42 (1H, s),8.83 (1H, d, J=4.8 Hz).

Production Example 249-2 Methyl4-(4-amino-3-chlorophenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxylate

Methyl 4-chloro-7-(2-methoxyethoxy)-6-quinolinecarboxylate (4.9 g),4-amino-3-chlorophenol (2.0 g), sodium hydride (550 mg) anddimethylformamide (20 ml) were stirred together at 100° C. for 2 hours.The mixture was returned to room temperature, water was added, andextraction was performed with ethyl acetate. Silica gel was added to theextract solution and the solvent was distilled off under reducedpressure. The silica gel was charged into a dry column packed withsilica gel, and purification was performed by column chromatography(hexane:ethyl acetate=1:1, followed by ethyl acetate) to obtain 3.2 g ofthe target substance as a violet solid.

¹H-NMR (DMSO-d₆) δ (ppm): 3.34 (3H, s), 3.72 (2H, t, J=4.4 Hz). 3.83(3H, s), 4.29 (2H, t, J=4.4 Hz), 5.44 (2H, s), 6.44 (1H. d, J=5.6 Hz),6.88 (1H, d, J=8.8 Hz), 7.00 (1H, dd, J=8.8 Hz, 2.4 Hz), 7.23 (1H, d,J=2.4 Hz), 7.49 (1H, s), 8.53 (1H, s), 8.63 (1H, d, J=5.6 Hz).

Production Example 249-3 Methyl4-{3-chloro-4-[(phenoxycarbonyl)amino]phenoxy}-7-(2-methoxyethoxy)-6-quinolinecarboxylate

Methyl4-(4-amino-3-chlorophenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxylate(3.2 g), pyridine (0.71 ml) and tetrahydrofuran (50 ml) were stirredwhile cooling on ice, and then 1.1 ml of phenyl chloroformate was addeddropwise. After 40 minutes, 0.8 ml of pyridine and 1.1 ml of phenylchloroformate were added and the mixture was stirred for an additional10 minutes. Water was added, extraction was performed with ethylacetate, and the extract solution was passed through a glass filtercoated with silica gel. The silica gel was washed with ethyl acetate,the solvent was distilled off under reduced pressure, hexane and ethylacetate were added to the residue and the solid was filtered out toobtain 3.2 g of a faint red solid.

¹H-NMR(CDCl₃) δ (ppm): 3.50 (3H, s), 3.80 (2H, t, J=4.4 Hz), 3.98 (3H,s), 4.37 (2H, t, J=4.4 Hz), 6.49 (1H, d, J=5.6 Hz), 7.17-7.30 (6H, m),7.40-7.52 (3H, m), 8.30-8.37 (1H, m), 8.66 (1H, d, J=5.6 Hz), 8.80 (1H,s).

Production Example 249-4 Methyl4-(3-chloro-4-{[(cyclopropylamino)carbonyl]amino}phenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxylate

Methyl4-{3-chloro-4-[(phenoxycarbonyl)amino]phenoxy}-7-(2-methoxyethoxy)-6-quinolinecarboxylate(3.2 g), cyclopropylamine (1.3 ml) and dimethylformamide (20 ml) werestirred together at 60° C. for 10 minutes. The mixture was returned toroom temperature, water was added, and extraction was performed withethyl acetate. Silica gel was added to the extract solution and thesolvent was distilled off under reduced pressure. The silica gel wascharged into a dry column packed with silica gel, and purification wasperformed by column chromatography (ethyl acetate, followed by ethylacetate:methanol=50:1, 20:1) to obtain 2.26 g of the target substance asa white powder.

¹H-NMR (DMSO-d₆) δ (ppm): 0.38-0.45 (2H, m), 0.61-0.69 (2H, m),2.50-2.58 (1H, m), 3.36 (3H, s), 3.73 (2H, t, J=4.4 Hz), 3.84 (3H, s),4.31 (2H, t, J=4.4 Hz), 6.51 (1H, d, J=5.2 Hz), 7.18 (1H, s), 7.24 (1H,dd, J=8.8 Hz, 2.4 Hz), 7.49 (1H, d, J=2.4 Hz), 7.52 (1H, s), 7.96 (1H,s), 8.26 (1H, d, J=8.8 Hz), 8.55 (1H, s), 8.67 (1H, d, J=5.2 Hz).

Production Example 249-54-(3-Chloro-4-{[(cyclopropylamino)carbonyl]amino}phenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxylicacid

Methyl4-(3-chloro-4-{[(cyclopropylamino)carbonyl]amino}phenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxylate(2.26 g), 2N aqueous sodium hydroxide (20 ml), methanol (20 ml) andtetrahydrofuran (20 ml) were stirred together at room temperature for 1hour. After adding 5N aqueous hydrochloric acid and distilling off 10 mlof the organic solvent, the precipitated solid was filtered out. Thesolid was washed with a methanol and water mixed solvent to obtain 2.0 gof the target substance as a faint red powder.

¹H-NMR (DMSO-d₆) δ (ppm): 0.38-0.45 (2H, m), 0.60-0.68 (2H, m),2.50-2.59 (1H, m), 3.34 (3H, s), 3.73 (2H, t, J=4.4 Hz), 4.30 (2H, t,J=4.4 Hz), 6.51 (1H, d, J=5.2 Hz), 7.23 (1H, dd, J=9.2 Hz, 2.8 Hz), 7.25(1H, s), 7.49 (1H, d, J=2.8 Hz), 7.50 (1H, s), 8.00 (1H, s), 8.25 (1H,d, J=9.2 Hz), 8.50 (1H, s), 8.66 (1H, d, J=5.2 Hz).

Example 250N6-(2-Fluoroethyl)-4-(3-chloro-4-{[(cyclopropylamino)carbonyl]amino}phenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxamide

The target substance was obtained using 2-fluoroethylaminehydrochloride, in the same manner as Example 249.

¹H-NMR (DMSO-d₆) δ (ppm): 0.38-0.45 (2H, m), 0.60-0.68 (2H, m),2.48-2.58 (1H, m), 3.35 (3H, s), 3.61 (1H, td, J=4.8 Hz, 4.8 Hz), 3.68(1H, td, J=4.8 Hz, 4.8 Hz), 3.78 (2H, t, J=4.8 Hz), 4.41 (2H, t, J=4.8Hz), 4.50 (1H, t, J=4.8 Hz), 4.62 (1H, t, J=4.8 Hz), 6.53 (1H, d, J=5.2Hz), 7.20 (1H, s), 7.24 (1H, dd, J=9.2 Hz, 2.4 Hz), 7.49 (1H, d, J=2.4Hz), 7.56 (1H, s), 7.98 (1H, s), 8.26 (1H, d, J=9.2 Hz), 8.59 (1H, t,J=4.8 Hz), 8.67 (1H, d, J=5.2 Hz), 8.70 (1H, s).

Example 251N6-Methoxy-4-(3-chloro-4-{[(cyclopropylamino)carbonyl]amino}phenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxamide

The target substance was obtained using O-methylhydroxylaminehydrochloride, in the same manner as Example 249.

¹H-NMR (DMSO-d₆) δ (ppm): 0.38-0.44 (2H, m), 0.62-0.98 (2H, m),2.50-2.60 (1H, m), 3.35 (3H, s), 3.73 (3H, s), 3.77 (2H, t, J=4.4 Hz),4.35 (2H, t, J=4.4 Hz), 6.52 (1H, d, J=5.2 Hz), 7.18 (1H, s), 7.22 (1H,dd, J=9.2 Hz, 2.4 Hz), 7.47 (1H, d, J=2.4 Hz), 7.52 (1H, s), 7.96 (1H,s), 8.26 (1H, d, J=9.2 Hz), 8.41 (1H, s), 8.66 (1H, d, J=5.2 Hz), 11.30(1H, s).

Example 2521-{5-[6-Cyano-7-(2-methoxyethoxy)-quinolin-4-ylsulfanyl]-thiophen-2-yl}-3-(thiazol-2-yl)urea

The title compound (45 mg) was obtained as a solid from4-(5-aminothiophen-2-ylsulfanyl)-7-(2-methoxyethoxy)-quinoline-6-carbonitrile(118 mg) and thiazol-2-ylcarbamic acid phenyl ester (77 mg), in the samemanner as Example 246.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.36 (3H, s), 3.75-3.78 (2H, m),4.40-4.42 (2H, m), 6.76-6.79 (1H, m), 6.80 (1H, d, J=5.2 Hz), 7.02-7.08(1H, m), 7.32-7.38 (1H, m), 7.35 (1H, d, J=4.0 Hz), 7.63 (1H, s), 8.62(1H, s), 8.70 (1H, d, J=5.2 Hz).

Production Example 252-17-(2-Methoxyethoxy)-4-thioxo-1,4-dihydroquinoline-6-carbonitrile

The title compound (9 g) was obtained as a solid from6-cyano-7-methoxyethoxy-1H-quinolin-4-one (10 g), in the same manner asProduction Example 226-1.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.35 (3H, s), 3.74-3.77 (2H, m),4.31-4.34 (2H, m), 7.16-7.19 (2H, m), 7.82 (1H, d, J=6.8 Hz), 8.86 (1H,s), 12.84 (1H, br s).

Production Example 252-27-(2-Methoxyethoxy)-4(5-nitrothiophen-2-ylsulfanyl)quinoline-6-carbonitrile

The title compound (2.2 g) was obtained as a solid from7-(2-methoxyethoxy)-4-thioxo-1,4-dihydroquinoline-6-carbonitrile (7.1 g)and 2-bromo-5-nitrothiophene (6.3 g), by the same procedure as inProduction Example 226-2.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.35 (3H, s), 3.75-3.78 (2H, m),4.41-4.44 (2H, m), 7.18 (1H, d, J=4.4 Hz), 7.68 (1H, d, J=4.8 Hz), 7.69(1H, s), 8.23 (1H, d, J=4.4 Hz), 8.70 (1H, s), 8.79 (1H, d, J=4.8 Hz).

Production Example 252-34-(5-Aminothiophen-2-ylsulfanyl)-7-(2-methoxyethoxy)quinoline-6-carbonitrile

The title compound (0.93 g) was obtained as a solid from7-(2-methoxyethoxy)-4-(5-nitrothiophen-2-ylsulfanyl)quinoline-6-carbonitrile(2.2 g), in the same manner as Production Example 226-3.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.35 (3H, s), 3.74-3.78 (2H, m),4.38-4.41 (2H, m), 5.98 (1H, d, J=3.6 Hz), 6.37 (2H, t, brs), 6.86 (1H,d, J=4.8 Hz), 7.07 (1H, d, J=3.6 Hz), 7.61 (1H, s), 8.54 (1H, s), 8.71(1H, d, J=4.8 Hz).

Example 2531-{5-[6-Cyano-7-(2-methoxyethoxy)-quinolin-4-ylsulfanyl]thiophen-2-yl}-3-(4-fluorophenyl)urea

The title compound (24 mg) was obtained as a solid from4-(5-amino-thiophen-2-ylsulfanyl)-7-(2-methoxyethoxy)-quinoline-6-carbonitrile(30 mg) and 4-fluorophenyl isocyanate, in the same manner as Example252.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.36 (3H, s), 3.75-3.78 (2H, m),4.39-4.43 (2H, m), 6.71 (1H, d, J=3.6 Hz), 6.80 (1H, d, J=4.8 Hz), 7.12(2H, t, J=9.2 Hz), 7.34 (1H, d, J=4.0 Hz), 7.43-7.47 (2H, m), 7.63 (1H,s), 8.62 (1H, s), 8.70 (1H, d, J=4.8 Hz), 8.97 (1H, br s), 10.23 (1H, brs).

Example 2541-{5-[6-Cyano-7-(2-methoxyethoxy)quinolin-4-ylsulfanyl]thiophen-2-yl}-3-(3-fluorophenyl)urea

The title compound (20 mg) was obtained as a solid from4-(5-amino-thiophen-2-ylsulfanyl)-7-(2-methoxyethoxy)-quinoline-6-carbonitrile(30 mg) and 3-fluorophenyl isocyanate, in the same manner as Example252.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.36 (3H, s), 3.75-3.78 (2H, m),4.39-4.43 (2H, m), 6.73 (1H, d, J=4.0 Hz), 6.81 (1H, d, J=4.8 Hz),6.78-6.85 (1H, m), 7.15-7.19 (1H, m), 7.27-7.32 (1H, m), 7.35 (1H, d,J=4.0 Hz), 7.40-7.45 (1H, m), 7.63 (1H, s), 8.62 (1H, s), 8.70 (1H, d,J=4.8 Hz), 9.18 (1H, br s), 10.30 (1H, br s).

Example 2551-{5-[6-Cyano-7-(2-methoxyethoxy)quinolin-4-ylsulfanyl]thiophen-2-yl}-3-cyclopropylurea

The title compound (15 mg) was obtained as a solid from4-(5-amino-thiophen-2-ylsulfanyl)-7-(2-methoxyethoxy)-quinoline-6-carbonitrile(35 mg) and cyclopropylamine, by the same procedure as in Example 252.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.41-0.46 (2H, m), 0.61-0.68 (2H, m),2.48-2.55 (1H, m), 3.36 (3H, s), 3.75-3.79 (2H, m), 4.39-4.43 (2H, m),6.63 (1H, d, J=4.0 Hz), 6.77 (1H, d, J=4.8 Hz), 6.79-7.84 (1H, m), 7.28(1H, d, J=4.0 Hz), 7.62 (1H, s), 8.60 (1H, s), 8.69 (1H, d, J=4.8 Hz),9.93 (1H, br s).

Example 2561-{5-[6-Cyano-7-(2-methoxyethoxy)quinolin-4-ylsulfanyl]thiophen-2-yl}-3-(2-fluorophenyl)urea

The title compound (15 mg) was obtained as a solid from4-(5-aminothiophen-2-ylsulfanyl)-7-(2-methoxyethoxy)quinoline-6-carbonitrile(38 mg) and 2-fluorophenyl isocyanate, in the same manner as Example252.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.36 (3H, s), 3.75-3.78 (2H, m),4.39-4.43 (2H, m), 6.72 (1H, d, J=4.0 Hz), 6.80 (1H, d, J=4.8 Hz),7.02-7.08 (1H, m), 7.12-7.16 (1H, m), 7.21-7.27 (1H, m), 7.36 (1H, d,J=4.0 Hz), 7.63 (1H, s), 7.99-8.04 (1H, m), 8.62 (1H, s), 8.70 (1H, d,J=4.8 Hz), 8.74-8.78 (1H, m), 10.45 (1H, brs).

Example 2571-{5-[6-Cyano-7-(2-methoxyethoxy)quinolin-4-ylsulfanyl]thiophen-2-yl}-3-phenylurea

The title compound (12 mg) was obtained as a solid from4-(5-aminothiophen-2-ylsulfanyl)-7-(2-methoxyethoxy)quinoline-6-carbonitrile(38 mg) and phenyl isocyanate, in the same manner as Example 252.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.36 (3H, s), 3.75-3.78 (2H, m),4.39-4.43 (2H, m), 6.71 (1H, d, J=4.0 Hz), 6.81 (1H, d, J=4.8 Hz),6.97-7.01 (1H, m), 7.28 (2H, t, J=7.6 Hz), 7.34 (1H, d, J=4.0 Hz), 7.44(2H, d, J=7.6 Hz), 7.63 (1H, s), 8.62 (1H, s), 8.70 (1H, d, J=4.8 Hz),8.94 (1H, br s), 10.21 (1H, br s).

Example 2581-{5-[6-Cyano-7-(2-methoxyethoxy)quinolin-4-ylsulfanyl]thiophen-2-yl}-3-(2,4-difluorophenyl)urea

The title compound (18 mg) was obtained as a solid from4-(5-aminothiophen-2-ylsulfanyl)-7-(2-methoxyethoxy)quinoline-6-carbonitrile(30 mg) and 2,4-difluorophenyl isocyanate, by the same procedure as inExample 252.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.35 (3H, s), 3.74-3.78 (2H, m),4.39-4.43 (2H, m), 6.71 (1H, d, J=4.0 Hz), 6.80 (1H, d, J=4.8 Hz),7.01-7.08 (1H, m), 7.29-7.34 (1H, m), 7.35 (1H, d, J=4.0 Hz), 7.63 (1H,s), 7.89-7.97 (1H, m), 8.62 (1H, s), 8.70 (1H, d, J=4.8 Hz), 8.73 (1H,br s), 10.44 (1H, br s).

Example 2591-{5-[6-Cyano-7-(2-methoxyethoxy)quinolin-4-ylsulfanyl]thiophen-2-yl}-3-(para-tolyl)urea

The title compound (28 mg) was obtained as a solid from4-(5-aminothiophen-2-ylsulfanyl)-7-(2-methoxyethoxy)quinoline-6-carbonitrile(30 mg) and para-tolyl isocyanate, by the same procedure as in Example252.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.23 (3H, s), 3.36 (3H, s), 3.75-3.78(2H, m), 4.39-4.43 (2H, m), 6.69 (1H, d, J=4.0 Hz), 6.80 (1H, d, J=4.8Hz), 7.08 (2H, d, J=8.0 Hz), 7.32 (2H, d, J=8.0 Hz), 7.33 (1H, d, J=4.0Hz), 7.63 (1H, s), 8.61 (1H, s), 8.70 (1H, d, J=4.8 Hz), 8.81 (1H, brs), 10.15 (1H, br s).

Example 2601-{5-[6-Cyano-7-(2-methoxyethoxy)quinolin-4-ylsulfanyl]-thiophen-2-yl}-3-(3-cyanophenyl)-urea

The title compound (33 mg) was obtained as a solid from4-(5-aminothiophen-2-ylsulfanyl)-7-(2-methoxyethoxy)quinoline-6-carbonitrile(30 mg) and 3-cyanophenyl isocyanate, by the same procedure as inExample 252.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.36 (3H, s), 3.75-3.78 (2H, m),4.39-4.43 (2H, m), 6.75 (1H, d, J=4.0 Hz), 6.80 (1H, d, J=4.8 Hz), 7.36(1H, d, J=4.0 Hz), 7.43-7.52 (2H, m), 7.63 (1H, s), 7.70-7.73 (1H, m),7.91-7.94 (1H, m), 8.62 (1H, s), 8.70 (1H, d, J=4.8 Hz), 9.30 (1H, brs), 10.44 (1H, br s).

Example 2611-{5-[6-Cyano-7-(2-methoxyethoxy)quinolin-4-ylsulfanyl]thiophen-2-yl}-3-(4-cyanophenyl)urea

The title compound (28 mg) was obtained as a solid from4-(5-aminothiophen-2-ylsulfanyl)-7-(2-methoxyethoxy)quinoline-6-carbonitrile(30 mg) and 4-cyanophenyl isocyanate, by the same procedure as inExample 252.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.35 (3H, s), 3.74-3.78 (2H, m),4.39-4.43 (2H, m), 6.76 (1H, d, J=4.0 Hz), 6.80 (1H, d, J=4.8 Hz), 7.36(1H, d, J=4.0 Hz), 7.61-7.66 (3H, m), 7.71-7.75 (2H, m), 8.62 (1H, s),8.70 (1H, d, J=4.8 Hz), 9.48 (1H, br s), 10.44 (1H, br s).

Example 262N-[4-(7-(2-Methoxyethoxy)-6-cyano-4-quinolyl)oxyphenyl-N′-(4-cyclopropyl)urea

The title compound (220 mg) was obtained as a solid from7-(2-methoxyethoxy)-6-cyano-4-(4-amino-3-chlorophenoxy)quinoline (380mg), by the same procedure as in Example 249-4.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.38-0.44 (2H, m), 0.63-0.69 (2H, m),2.53-2.60 (1H, m), 3.36 (3H, s), 3.76-3.79 (2H, m), 4.40-4.43 (2H, m),6.58 (1H, d, J=5.2 Hz), 7.19 (1H, d, J=2.8 Hz), 7.25 (1H, dd, J=2.8,J=8.8 Hz), 7.50 (1H, d, J=2.8 Hz), 7.63 (1H, s), 7.98 (1H, s), 8.28 (1H,d, J=8.8 Hz), 8.73 (1H, d, J=5.2 Hz), 8.74 (1H, s).

Production Example 262-17-(2-Methoxyethoxy)-6-cyano-4-(4-amino-3-chlorophenoxy)quinoline

The title compound (380 mg) was obtained as a solid from4-chloro-7-methoxyethoxy-6-cyanoquinoline (800 mg) obtained by apublicly known method, by the same procedure as in Production Example395-1.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.36 (3H, s), 3.75-3.78 (2H, m),4.39-4.41 (2H, m), 5.46 (2H, br s), 6.51 (1H, d, J=5.2 Hz), 6.89 (1H, d,J=8.8 Hz), 7.01 (1H, dd, J=2.8, 8.8 Hz), 7.24 (1H, d, J=2.8 Hz), 7.60(1H, s), 8.70 (1H, d, J=5.2 Hz), 8.71 (1H, s).

Example 263(4-{4-[3-(4-Fluorophenyl)ureido]phenoxy}-7-methoxyquinolin-6-yl)carbamicacid benzyl ester

The title compound (380 mg) was obtained as a solid from[4-(4-aminophenoxy)-7-methoxyquinolin-6-yl]carbamic acid benzyl ester(330 mg) and 4-fluorophenyl isocyanate, in the same manner as Example10.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.97 (3H, s), 5.19 (2H, s), 6.42 (1H,d, J=5.2 Hz), 7.11 (2H, t, J=8.8 Hz), 7.19 (2H, d, J=8.8 Hz), 7.29-7.49(8H, m), 7.57 (2H, d, J=8.8 Hz), 8.49 (1H, d, J=5.2 Hz), 8.67 (1H, s),8.80 (1H, br s), 8.87 (1H, br s), 8.98 (1H, s).

The intermediates were synthesized in the following manner.

Production Example 263-1(7-Methoxy-4-oxo-1,4-dihydroquinolin-6-yl)carbamic acid benzyl ester

After dissolving 7-methoxy-4-oxo-1,4-dihydroquinoline-6-carboxylic acid(2.58 g) in N,N-dimethylformamide (50 ml), there were added benzylalcohol (3.29 ml), diphenylphosphoryl azide 2.51 ml) and triethylamine(1.63 ml), and the mixture was heated and stirred at 95° C. for 5 hours.The reaction solution was poured into saturated brine and extracted withethyl acetate, and the organic layer was dried over magnesium sulfateand concentrated. The obtained residue was subjected to NH silica gelcolumn chromatography and eluted with a solvent (ethylacetate:methanol=5:1) to obtain the title compound (2.03 g) as a solid.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.85 (3H, s), 5.14 (2H, s), 5.93 (1H,d, J=7.2 Hz), 7.07 (1H, s), 7.39-7.43 (5H, m), 7.74-7.81 (1H, m), 8.30(1H, br s), 8.75 (1H, s), 11.97 (1H, br s).

Production Example 263-2 (4-Chloro-7-methoxyquinolin-6-yl)carbamic acidbenzyl ester

(7-Methoxy-4-oxo-1,4-dihydroquinolin-6-yl)carbamic acid benzyl ester (2g) was added to a mixture of thionyl chloride (20 ml) andN,N-dimethylformamide (0.5 ml), and the mixture was heated to reflux for2 hours. After completion of the reaction, the thionyl chloride wasdistilled off, and a procedure of toluene addition and concentration wasrepeated 3 times to obtain the title compound (2.4 g) as a solid.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.98 (3H, s), 5.22 (2H, s), 7.26-7.49(6H, m), 7.55 (1H, d, J=5.2 Hz), 8.63 (1H, d, J=5.2 Hz), 8.65 (1H, s),9.12 (1H, br s).

Production Example 263-3[4-(4-Aminophenoxy)-7-methoxyquinolin-6-yl]carbamic acid benzyl ester

A 4-phenoxyquinoline compound (465 mg) was obtained from(4-chloro-7-methoxyquinolin-6-yl)carbamic acid benzyl ester (2.4 g) and4-nitrophenol (2.07 g), in the same manner as Production Example 7. The4-phenoxyquinoline compound (450 mg) was reduced in the same manner asProduction Example 8 to obtain the title compound (330 mg) as a solid.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.96 (3H, s), 5.15 (2H, br s), 5.18(2H, s), 6.34 (1H, d, J=5.2 Hz), 6.65 (2H, d, J=8.4 Hz), 6.90 (2H, d,J=8.4 Hz), 7.29-7.46 (6H, m), 8.45 (1H, d, J=5.2 Hz), 8.65 (1H, s), 8.95(1H, s).

Example 2641-[4-(6-Amino-7-methoxyquinolin-4-yloxy)phenyl]-3-(4-fluorophenyl)urea

After dissolving(4-{4-[3-(4-fluorophenyl)ureido]phenoxy}-7-methoxyquinolin-6-yl)carbamicacid benzyl ester (100 mg) in a mixture of tetrahydrofuran (10ml)-methanol (10 ml), 10% palladium carbon (10 mg) was added and themixture was stirred for 7 hours at room temperature under hydrogen gasat 1 atmosphere. The reaction solution was filtered through celite andthe filtrate was concentrated to obtain the title compound (60 mg) as asolid.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.94 (3H, s), 5.44 (2H, s), 6.34 (1H,d, J=5.2 Hz), 7.07-7.15 (4H, m), 7.23 (1H, s), 7.23 (1H, s), 7.43-7.48(2H, m), 7.53 (2H, d, J=8.8 Hz), 8.25 (1H, d, J=5.2 Hz), 8.83 (1H, brs), 8.87 (1H, br s).

Example 265N-(4-{4-[3-(4-Fluorophenyl)ureido]phenoxy}-7-methoxyquinolin-6-yl)acetamide

After dissolving1-[4-(6-amino-7-methoxyquinolin-4-yloxy)phenoxy]-3-(4-fluorophenyl)urea(50 mg) in pyridine (5 ml), acetic anhydride (0.5 ml) was added and themixture was allowed to stand at room temperature for 12 hours. Thereaction solution was poured into saturated brine and extracted withethyl acetate, and the organic layer was dried over magnesium sulfateand concentrated to obtain the title compound (50 mg) as a solid.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.17 (3H, s), 4.01 (3H, s), 6.41 (1H,d, J=5.6 Hz), 7.11 (2H, t, J=8.8 Hz), 7.18 (2H, d, J=8.8 Hz), 7.42-7.49(3H, m), 7.57 (2H, d, J=8.8 Hz), 8.49 (1H, d, J=5.6 Hz), 8.78 (1H, brs), 8.85 (1H, br s), 8.98 (1H, s), 9.45 (1H, s).

Example 266N-(4-{4-[3-(4-Fluorophenyl)ureido]phenoxy}-7-methoxyquinolin-6-yl)methanesulfoneamide

After dissolving1-[4-(6-amino-7-methoxyquinolin-4-yloxy)phenoxy]-3-(4-fluorophenyl)urea(50 mg) in tetrahydrofuran (3 ml), triethylamine (0.3 ml) andmethanesulfonyl chloride (14 μl) were added and the mixture was stirredat room temperature for 1 hour. The reaction solution was poured intosaturated aqueous ammonium chloride solution and extracted with ethylacetate, and the organic layer was washed with saturated brine and driedover magnesium sulfate. The organic layer was concentrated and theobtained residue was subjected to silica gel column chromatography forelution with a solvent (ethyl acetate:methanol=5:1) to obtain the titlecompound (13 mg) as a solid.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.05 (3H, s), 3.98 (3H, s), 6.43 (1H,d, J=5.2 Hz), 7.11 (2H, t, J=8.8 Hz), 7.19 (2H, d, J=8.8 Hz), 7.43-7.48(3H, m), 7.57 (2H, d, J=8.8 Hz), 8.12 (1H, s), 8.53 (1H, d, J=5.2 Hz),8.76 (1H, br s), 8.84 (1H, br s), 9.31 (1H, br).

Example 267(4-{3-Fluoro-4-[3-(4-fluorophenyl)ureido]phenoxy}-7-methoxyquinolin-6-yl)carbamicacid benzyl ester

The title compound (180 mg) was obtained as a solid from[4-(4-amino-3-fluorophenoxy)-7-methoxyquinolin-6-yl]carbamic acid benzylester (166 mg) and 4-fluorophenyl isocyanate, in the same manner asExample 10.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.97 (3H, s), 5.18 (2H, s), 6.51 (1H,d, J=5.2 Hz), 7.05-7.09 (1H, m), 7.12 (2H, t,

J=8.8 Hz), 7.29-7.41 (4H, m), 7.42-7.49 (5H, m), 8.20 (1H, t, J=8.8 Hz),8.52 (1H, d, J=5.2 Hz), 8.62-8.64 (1H, m), 8.65 (1H, s), 8.99 (1H, s),9.12 (1H, br s).

The intermediates were synthesized in the following manner.

Production Example 267-1[4-(3-Fluoro-4-nitrophenoxy)-7-methoxyquinolin-6-yl]carbamic acid benzylester

(4-Chloro-7-methoxyquinolin-6-yl)carbamic acid benzyl ester (1.58 g) wasadded to 1-methyl-2-pyrrolidone (5 ml), and then 3-fluoro-4-nitrophenol(0.87 g) and N,N-diisopropylethylamine (1.2 ml) were added and themixture was heated and stirred at 130° C. for 6 hours. The reactionsolution was poured into saturated aqueous sodium bicarbonate andextracted with ethyl acetate, and the organic layer was washed withsaturated brine and dried over magnesium sulfate. The organic layer wasconcentrated and the obtained residue was subjected to NH silica gelcolumn chromatography for elution with a solvent (ethyl acetate) toobtain the title compound (188 mg) as a solid.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.98 (3H, s), 5.16 (2H, s), 6.96 (1H,d, J=5.2 Hz), 7.16-7.21 (1H, m), 7.28-7.43 (5H, m), 7.50 (1H, s),7.53-7.58 (1H, m), 8.26 (1H, t, J=8.8 Hz), 8.51 (1H, s), 8.66 (1H, d,J=5.2 Hz), 9.04 (1H, br s).

Production Example 267-2[4-(4-Amino-3-fluorophenoxy)-7-methoxyquinolin-6-yl]carbamic acid benzylester

The title compound (170 mg) was obtained as a solid by reduction of[4-(3-fluoro-4-nitrophenoxy)-7-methoxyquinolin-6-yl]carbamic acid benzylester (188 mg) in an ethanol/water mixed solvent using iron and ammoniumchloride, according to the same procedure as in Production Example 10.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.96 (3H, s), 5.18 (4H, br s), 6.40(1H, d, J=5.2 Hz), 6.79-6.86 (2H, m), 7.04 (1H, dd, J=2.4 Hz, J=12 Hz),7.29-7.46 (6H, m), 8.47 (1H, d, J=5.2 Hz), 8.63 (1H, s), 8.95 (1H, brs).

Example 2681-[4-(6-Amino-7-methoxyquinolin-4-yloxy)-2-fluorophenyl]-3-(4-fluorophenyl)urea

The title compound (125 mg) was obtained as a solid from(4-{3-fluoro-4-[3-(4-fluorophenyl)ureido]phenoxy}-7-methoxyquinolin-6-yl)carbamicacid benzyl ester (180 mg), in the same manner as Example 264.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.94 (3H, s), 5.45 (2H, br s), 6.45(1H, d, J=5.2 Hz), 6.96-7.01 (1H, m), 7.12 (2H, t, J=8.8 Hz), 7.17-7.26(3H, m), 7.42-7.48 (2H, m), 8.13 (1H, t, J=9.2 Hz), 8.29 (1H, d, J=5.2Hz), 8.58 (1H, br s), 9.10 (1H, br s).

Example 269N-(4-{3-Fluoro-4-[3-(4-fluorophenyl)ureido]phenoxy}-7-methoxyquinolin-6-yl)acetamide

The title compound (50 mg) was obtained as a solid from1-[4-(6-amino-7-methoxyquinolin-4-yloxy)-2-fluorophenyl]-3-(4-fluorophenyl)urea(60 mg), in the same manner as Example 265.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.16 (3H, s), 4.01 (3H, s), 6.50 (1H,d, J=5.2 Hz), 7.05-7.09 (1H, m), 7.12 (2H, t, J=8.8 Hz), 7.33 (1H, dd,J=2.8 Hz, J=12 Hz), 7.43-7.49 (3H, m), 8.16-8.23 (1H, m), 8.52 (1H, d,J=5.2 Hz), 8.62 (1H, br s), 8.96 (1H, br s), 9.12 (1H, br s), 9.45 (1H,br s).

Example 270{4-[3-Fluoro-4-(3-(thiazol-2-yl)ureido)phenoxy]-7-methoxyquinolin-6-yl}carbamicacid benzyl ester

[4-(4-Amino-3-fluorophenoxy)-7-methoxyquinolin-6-yl]carbamic acid benzylester (100 mg) and thiazolyl-2-ylcarbamic acid phenyl ester (79 mg) wereheated in dimethylsulfoxide (1 ml) at 80° C., in the same manner asExample 224, to obtain the title compound (38 mg) as a solid.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.97 (3H, s), 5.19 (2H, s), 6.53 (1H,d, J=5.2 Hz), 7.09-7.13 (1H, m), 7.14 (1H, d, J=3.6 Hz), 7.29-7.41 (5H,m), 7.42-7.46 (3H, m), 8.20 (1H, t, J=9.2 Hz), 8.53 (1H, d, J=5.2 Hz),8.65 (1H, s), 9.00 (1H, br s), 9.04 (1H, br), 10.83 (1H, brs).

Example 2711-[4-(6-Amino-7-methoxyquinolin-4-yloxy)-2-fluorophenyl]-3-(thiazol-2-yl)urea

After adding{4-[3-fluoro-4-(3-(thiazol-2-yl)ureido)phenoxy]-7-methoxyquinolin-6-yl}carbamicacid benzyl ester (100 mg) to a mixture of trifluoroacetic acid (3 ml)and thioanisole (0.1 ml), the mixture was heated and stirred at 60° C.for 2 hours.

The solvent was distilled off and the residue was subjected to NH silicagel column chromatography for elution with a solvent (ethylacetate:methanol=10:1) to obtain the title compound (23 mg) as a solid.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.94 (3H, s), 5.47 (2H, br s), 6.48(1H, d, J=5.2 Hz), 6.99-7.03 (1H, m), 7.13 (1H, d, J=3.6 Hz), 7.17 (1H,s), 7.23-7.31 (2H, m), 7.38 (1H, d, J=3.6 Hz), 8.13 (1H, t, J=8.8 Hz),8.29 (1H, d, J=5.2 Hz), 8.97 (1H, br), 10.80 (1H, br).

Example 272N-{4-[3-Fluoro-4-(3-(thiazol-2-yl)ureido)phenoxy]-7-methoxyquinolin-6-yl}acetamide

The title compound (4 mg) was obtained as a solid from1-[4-(6-amino-7-methoxyquinolin-4-yloxy)-2-fluorophenyl]-3-(thiazol-2-yl)urea(15 mg), in the same manner as Example 265.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.15 (3H, s), 4.02 (3H, s), 6.53 (1H,d, J=5.2 Hz), 7.07-7.12 (1H, m), 7.12 (1H, d, J=3.6 Hz), 7.34-7.41 (2H,m), 7.45 (1H, s), 8.19 (1H, t, J=9.2 Hz), 8.53 (1H, d, J=5.2 Hz),8.95-8.98 (1H, m), 9.07 (1H, br), 9.45 (1H, br s).

Example 273N-{4-[3-Fluoro-4-(3-(thiazol-2-yl)ureido)phenoxy]-7-methoxyquinolin-6-yl}methanesulfoneamide

The title compound (5 mg) was obtained as a solid from1-[4-(6-amino-7-methoxyquinolin-4-yloxy)-2-fluorophenyl]-3-(thiazol-2-yl)urea(50 mg), in the same manner as Example 266.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.06 (3H, s), 4.00 (3H, s), 6.55 (1H,d, J=5.2 Hz), 7.09-7.16 (2H, m), 7.25-7.35 (1H, m), 7.39 (1H, d, J=3.2Hz), 7.49 (1H, s), 8.10 (1H, s), 8.21 (1H, t, J=9.2 Hz), 8.57 (1H, d,J=5.2 Hz), 9.02 (1H, br s), 9.32 (1H, br s), 10.78 (1H, br s).

Example 274{4-[4-(Cyclopropylureido)-3-fluorophenoxy]-7-methoxyquinolin-6-yl}carbamicacid benzyl ester

[4-(4-Amino-3-fluorophenoxy)-7-methoxyquinolin-6-yl]carbamic acid benzylester (100 mg) and cyclopropylcarbamic acid phenyl ester (64 mg) wereheated and stirred in dimethylsulfoxide (0.7 ml) at 85° C. for 5 hoursand 40 minutes, in the same manner as Example 224, to obtain the titlecompound (11 mg) as a solid.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.37-0.41 (2H, m), 0.60-0.65 (2H, m),2.50-2.56 (1H, m), 3.95 (3H, s), 5.16 (2H, s), 6.46 (1H, d, J=5.2 Hz),6.77-6.80 (1H, m), 6.99-7.03 (1H, m), 7.23-7.45 (7H, m), 8.16 (1H, t,J=9.2 Hz), 8.19 (1H, s), 8.49 (1H, d, J=5.2 Hz), 8.63 (1H, s), 8.97 (1H,s).

Example 275N-{4-[4-(Cyclopropylureido)3-fluorophenoxy]-7-methoxyquinolin-6-yl}acetamide

{4-[4-(cyclopropylureido)-3-fluorophenoxy]-7-methoxyquinolin-6-yl}carbamicacid benzyl ester (11 mg) was heated and stirred in a mixture oftrifluoroacetic acid (3 ml) and thioanisole (0.5 ml) at 60° C., in thesame manner as Example 264, for debenzylation. The resulting aminocompound was acetylated in the same manner as Example 265 to obtain thetitle compound (2 mg) as a solid.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.36-0.40 (2H, m), 0.58-0.63 (2H, m),2.14 (3H, s), 2.46-2.55 (1H, m), 3.99 (3H, s), 6.44 (1H, d, J=5.2 Hz),6.77 (1H, d, J=2.8 Hz), 6.97-7.01 (1H, m), 7.23 (1H, dd, J=2.8 Hz,J=11.6 Hz), 7.41 (1H, s), 8.15 (1H, t, J=8.8 Hz), 8.17 (1H, br s), 8.48(1H, d, J=5.2 Hz), 8.93 (1H, s), 9.42 (1H, s).

Example 2764-[4-(Cyclopropylureido)-2-methylphenoxy]-7-methoxyquinoline-6-carboxylicacid amide

The title compound (61 mg) was obtained as a solid from[4-(6-carbamoyl-7-methoxyquinolin-4-yloxy)-3-methylphenyl]carbamic acidphenyl ester (100 mg) and cyclopropylamine, in the same manner asExample 11.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.37-0.41 (2H, m), 0.59-0.65 (2H, m),2.04 (3H, s), 2.49-2.55 (1H, m), 4.01 (3H, s), 6.26 (1H, d, J=5.2 Hz),6.41-6.47 (1H, m), 7.05 (1H, d, J=8.8 Hz), 7.35 (1H, dd, J=2.4 Hz, J=8.8Hz), 7.42 (1H, d, J=2.4 Hz), 7.48 (1H, s), 7.71 (1H, br s), 7.84 (1H, brs), 8.27-8.42 (1H, m), 8.59 (1H, d, J=5.2 Hz), 8.69 (1H, s).

The intermediates were synthesized in the following manner.

Production Example 276-14-(4-Amino-2-methylphenoxy)-7-methoxyquinoline-6-carboxylic acid amide

The title compound (430 mg) was obtained as a solid from4-chloro-7-methoxyquinoline-6-carboxylic acid amide (1 g) and4-amino-2-methylphenol, in the same manner as Production Example 458-1.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.93 (3H, s), 4.01 (3H, s), 5.06-5.09(2H, m), 6.27 (1H, d, J=5.2 Hz), 6.49 (1H, dd, J=2.8 Hz, J=8.4 Hz), 6.54(1H, d, J=2.8 Hz), 6.84 (1H, d, J=8.4 Hz), 7.47 (1H, s), 7.71 (1H, brs), 7.83 (1H, br s), 8.59 (1H, d, J=5.2 Hz), 8.69 (1H, s).

Production Example 276-2[4-(6-Carbamoyl-7-methoxyquinolin-4-yloxy)-3-methylphenyl]carbamic acidphenyl ester

The title compound (112 mg) was obtained as a solid from4-(4-amino-2-methylphenoxy)-7-methoxyquinoline-6-carboxylic acid amide(330 mg) and phenyl chlorocarbonate, in the same manner as ProductionExample 17.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.08 (3H, s), 4.02 (3H, s), 6.30 (1H,d, J=5.2 Hz), 7.19-7.55 (9H, m), 7.73 (1H, br s), 7.85 (1H, br s), 8.62(1H, d, J=5.2 Hz), 8.71 (1H, s), 10.33 (1H, br s).

Example 2771-(3-Fluorophenyl)-3-[4-(6-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl]urea

The title compound (118 mg) was obtained as a solid from4-(6-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenylamine (90mg) and 3-fluorophenyl isocyanate, in the same manner as Example 10.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 6.74-6.80 (1H, m), 7.11-7.15 (1H, m),7.20 (2H, d, J=8.8 Hz), 7.23 (1H, s), 7.29 (1H, t, J=7.6 Hz), 7.34-7.38(1H, m), 7.46-7.51 (1H, d, m), 7.52 (2H, d, J=8.8 Hz), 7.87-7.92 (1H,m), 8.08 (1H, d, J=8.0 Hz), 8.31 (1H, s), 8.63-8.66 (1H, m), 8.82 (1H,br s), 8.93 (1H, br s), 12.78 (1H, br s).

The intermediates were synthesized in the following manner.

Production Example 277-14-(4-Nitrophenoxy)-6-(pyridin-2-yl)-7-H-pyrrolo[2,3-d]pyrimidine

The title compound (1.0 g) was obtained as a solid from4-chloro-6-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine (0.8 g) andnitrophenol (1.45 g), by the same procedure as in Production Example 7.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 7.33 (1H, s), 7.37 (1H, dd, J=4.8 Hz,J=7.2 Hz), 7.59 (2H, d, J=9.2 Hz), 7.88-7.94 (1H, m), 8.12 (1H, d, J=7.2Hz), 8.33 (2H, d, J=9.2 Hz), 8.38 (1H, s), 8.66 (1H, d, J=4.8 Hz), 12.92(1H, br s).

Production Example 277-24-(6-(Pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenylamine

The title compound (0.4 g) was obtained as a solid from4-(4-nitrophenoxy)-6-(pyridin-2-yl)-7-H-pyrrolo[2,3-d]pyrimidine (1.0g), in the same manner as Production Example 8.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 5.06 (2H, br s), 6.60 (2H, d, J=8.8Hz), 6.90 (2H, d, J=8.8 Hz), 7.07 (1H, s), 7.32-7.36 (1H, m), 7.86-7.91(1H, m), 8.03 (1H, d, J=8.0 Hz), 8.29 (1H, s), 8.64 (1H, d, J=4 Hz),12.71 (1H, br s).

Example 2781-(4-Fluorophenyl)-3-[4-(6-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl]urea

The title compound (120 mg) was obtained as a solid from4-(6-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenylamine (100mg) and 4-fluorophenyl isocyanate, in the same manner as Example 10.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 7.11 (2H, t, J=8.8 Hz), 7.19 (2H, d,J=8.8 Hz), 7.22 (1H, s), 7.35 (1H, dd, J=7.2 Hz, J=7.6 Hz), 7.43-7.48(2H, m), 7.51 (2H, d, J=8.8 Hz), 7.87-7.92 (1H, m), 8.08 (1H, d, J=8.0Hz), 8.32 (1H, s), 8.64-8.66 (1H, m), 8.73 (1H, br s), 8.75 (1H, br s),12.78 (1H, br s).

Example 2791-[4-(6-(Pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)-phenyl]-3-(thiazol-2-yl)urea

4-(6-(Pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenylamine (100mg) and (thiazol-2-yl)carbamic acid phenyl ester (116 mg) were heatedand stirred in dimethylsulfoxide (2.5 ml) at 80° C. for 1 hour, in thesame manner as Example 224, to obtain the title compound (110 mg) as asolid.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 7.10 (1H, d, J=3.6 Hz), 7.23 (2H, d,J=8.8 Hz), 7.24 (1H, s), 7.34-7.40 (2H, m), 7.55 (2H, d, J=8.8 Hz),7.87-7.93 (1H, m), 8.09 (1H, d, J=8.0 Hz), 8.32 (1H, s), 8.63-8.67 (1H,m), 9.06 (1H, br s), 12.79 (1H, br s).

Example 2801-(4-Fluorophenyl)-3-[2-fluoro-4-(6-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)-phenyl]-urea

The title compound (110 mg) was obtained as a solid from2-fluoro-4-(6-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenylamine(100 mg) and 4-fluorophenyl isocyanate, by the same procedure as inExample 10.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 7.07-7.16 (3H, m), 7.28 (1H, s),7.33-7.38 (2H, m), 7.42-7.48 (2H, m), 7.87-7.93 (1H, m), 8.08-8.14 (2H,m), 8.33 (1H, s), 8.53-8.56 (1H, m), 8.64-8.66 (1H, m), 9.08 (1H, br s),12.83 (1H, br s).

The intermediates were synthesized in the following manner.

Production Example 280-14-(3-Fluoro-4-nitrophenoxy)-6-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine

The title compound (0.75 g) was obtained as a solid from the4-chloro-6-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine (0.7 g) describedin WO9702266 and PCT/EP96/02728 and fluoronitrophenol (0.95 g), in thesame manner as Production Example 7.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 7.34-7.45 (3H, m), 7.74 (1H, dd,J=2.4 Hz, J=12.4 Hz), 7.89-7.94 (1H, m), 8.12 (1H, d, J=8.0 Hz), 8.28(1H, t, J=8.8 Hz), 8.41 (1H, s), 8.65-8.68 (1H, m), 12.96 (1H, br s).

Production Example 280-22-Fluoro-4-(6-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenylamine

The title compound (450 mg) was obtained as a solid from4-(3-fluoro-4-nitrophenoxy)-6-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine(750 mg), by the same procedure as in Production Example 8.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 5.10 (2H, br s), 6.79-6.83 (2H, m),7.01-7.05 (1H, m), 7.16 (1H, s), 7.32-7.38 (1H, m), 7.86-7.92 (1H, m),8.06 (1H, d, J=7.6 Hz), 8.31 (1H, s), 8.64 (1H, d, J=4.4 Hz), 12.75 (1H,br s).

Example 2811-(3-Fluorophenyl)-3-[2-fluoro-4-(6-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl]urea

The title compound (30 mg) was obtained as a solid from2-fluoro-4-(6-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenylamine(100 mg) and 3-fluorophenyl isocyanate, in the same manner as Example10.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 6.76-6.83 (1H, m), 7.11 (2H, d, J=8.8Hz), 7.27-7.39 (4H, m), 7.48-7.53 (1H, m), 7.87-7.94 (1H, m), 8.11 (2H,d, J=8.8 Hz), 8.34 (1H, s), 8.61-8.65 (1H, m), 8.66 (1H, br d, J=4.0Hz), 9.27 (1H, br s), 12.83 (1H, br s).

Example 2821-[2-Fluoro-4-(6-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl]-3-(thiazol-2-yl)urea

The title compound (100 mg) was obtained as a solid from2-fluoro-4-(6-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenylamine(100 mg) and (thiazol-2-yl)carbamic acid phenyl ester (109 mg), by thesame procedure as in Example 224.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 7.07-7.17 (2H, m), 7.29 (1H, s),7.35-7.44 (3H, m), 7.87-7.95 (1H, m), 8.08-8.15 (2H, m), 8.34 (1H, s),8.66 (1H, br d, J=4.0 Hz), 8.99 (1H, br), 10.81 (1H, brs), 12.83 (1H,brs).

Example 2831-Cyclopropyl-3-[2-fluoro-4-(6-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl]urea

The title compound (15 mg) was obtained as a solid from2-fluoro-4-(6-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenylamine(75 mg) and cyclopropylcarbamic acid phenyl ester (66 mg), in the samemanner as Example 224.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.37-0.42 (2H, m), 0.60-0.66 (2H, m),2.49-2.57 (1H, m), 6.76 (1H, d, J=2.4 Hz), 7.01-7.05 (1H, m), 7.24-7.29(2H, m), 7.33-7.37 (1H, m), 7.86-7.92 (1H, m), 8.05-8.12 (2H, m),8.13-8.16 (1H, m), 8.32 (1H, s), 8.62-8.66 (1H, m), 12.79 (1H, br s).

Example 2847-((2R)-2-Hydroxy-3-(pyrrolidin-1-yl)propoxy)-4-(1H-indol-5-yloxy)quinoline-6-carbonitrile

The title compound (0.56 g) was obtained as a solid from4-(1H-indol-5-yloxy)-(2R)-7-oxiranylmethoxyquinoline-6-carbonitrile(0.73 g), in the same manner as Example 454.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.61-2.72 (4H, m), 2.44-2.58 (6H, m),2.68-2.73 (1H, m), 3.99-4.06 (1H, m), 4.20 (1H, dd, J=6.0 Hz, J=10.4Hz), 4.29 (1H, dd, J=3.6 Hz, J=10.4 Hz), 5.02 (1H, br s), 6.42 (1H, d,J=5.2 Hz), 6.44-6.48 (1H, m), 6.99 (1H, dd, J=1.6 Hz, J=8.4 Hz),7.43-7.47 (2H, m), 7.51 (1H, d, J=8.4 Hz), 7.59 (1H, s), 8.65 (1H, d,J=5.2 Hz), 8.77 (1H, s).

The intermediates were synthesized in the following manner.

Production Example 284-14-(1H-Indol-5-yloxy)-(2R)-7-oxiranylmethoxyquinoline-6-carbonitrile

The title compound (0.73 g) was obtained as a solid from4-(1H-indol-5-yloxy)-7-hydroxyquinoline-6-carbonitrile (1 g) using(2R)-oxiran-2-ylmethyl-4-methyl-1-benzene sulfonate, by the sameprocedure as in Example 7.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.82 (1H, dd, J=2.4 Hz, J=4.8 Hz),2.91 (1H, t, J=4.8 Hz), 3.44-3.49 (1H, m), 4.17 (1H, dd, J=6.4 Hz,J=11.6 Hz), 4.71 (1H, dd, J=2.4 Hz, J=11.6 Hz), 6.44 (1H, d, J=5.2 Hz),6.46-6.48 (1H, m), 6.99 (1H, dd, J=2.4 Hz, J=8.8 Hz), 7.44-7.46 (2H, m),7.52 (1H, d, J=8.8 Hz), 7.62 (1H, s), 8.67 (1H, d, J=5.2 Hz), 8.82 (1H,s), 11.31 (1H, br s).

Example 2855-[6-Cyano-7-((2R)-2-hydroxy-3-(pyrrolidin-1-yl)propoxy)quinolin-4-yloxy]indole-1-carboxylicacid cyclopropylamide

7-((2R)-2-Hydroxy-3-(pyrrolidin-1-yl)propoxy)-4-(1H-indol-5-yloxy)quinoline-6-carbonitrile(0.56 g) was silyletherified using triethylsilyl chloride and imidazoleto obtain 0.48 g of the target substance. Following the same procedureas in Example 310, an amide compound was obtained from the triethylsilylether compound (0.2 g), and this was deprotected at 50° C. in a mixtureof acetic acid, tetrahydrofuran and water to obtain the title compound(35 mg) as a solid.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.58-0.63 (2H, m), 0.71-0.76 (2H, m),1.84-1.94 (2H, m), 1.98-2.06 (2H, m), 2.73-2.79 (1H, m), 3.07-3.16 (2H,m), 3.33-3.38 (2H, m), 3.57-3.64 (2H, m), 4.28-4.36 (3H, m), 6.55 (1H,d, J=5.6 Hz), 6.70 (1H, d, J=3.6 Hz), 7.19 (1H, dd, J=2.4 Hz, J=8.8 Hz),7.53 (1H, d, J=2.4 Hz), 7.66 (1H, s), 7.88 (1H, d, J=3.6 Hz), 8.32 (1H,d, J=2.8 Hz), 8.35 (1H, d, J=8.8 Hz), 8.74 (1H, d, J=5.6 Hz), 8.87 (1H,s).

Example 2865-[6-Cyano-7-(3-(pyrrolidin-1-yl)propoxy)quinolin-4-yloxy]indole-1-carboxylicacid cyclopropylamide

The title compound (35 mg) was obtained as a solid from4-(1H-indol-5-yloxy)-7-(3-(pyrrolidin-1-yl)propoxy)quinoline-6-carbonitrile(150 mg), in the same manner as Example 310.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.59-0.64 (2H, m), 0.71-0.76 (2H, m),1.64-1.72 (4H, m), 1.95-2.03 (2H, m), 2.38-2.48 (4H, m), 2.59 (2H, d,J=6.8 Hz), 2.74-2.81 (1H, m), 4.33 (2H, d, J=6.4 Hz), 6.47 (1H, d, J=5.2Hz), 6.68 (1H, d, J=3.6 Hz), 7.19 (1H, dd, J=2.4 Hz, 8.8 Hz), 7.52 (1H,d, J=2.4 Hz), 7.58 (1H, s), 7.90 (1H, d, J=3.6 Hz), 8.23 (1H, d, J=2.8Hz), 8.35 (1H, d, J=8.8 Hz), 8.68 (1H, d, J=5.2 Hz), 8.79 (1H, s).

Example 2875-[6-Cyano-7-(2-methoxyethoxy)quinolin-4-yloxy]indole-1-carboxylic acidcyclopropylamide

The title compound (210 mg) was obtained as a solid from4-(1H-indol-5-yloxy)-7-(2-methoxyethoxyquinoline-6-carbonitrile (450mg), in the same manner as Example 310.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.59-0.65 (2H, m), 0.71-0.77 (2H, m),2.74-2.82 (1H, m), 3.76-3.80 (2H, m), 0.59-0.65 (2H, m), 4.39-4.43 (2H,m), 6.47 (1H, d, J=5.2 Hz), 6.68 (1H, d, J=3.6 Hz), 7.19 (1H, dd, J=2.4Hz, J=8.8 Hz), 7.52 (1H, d, J=2.4 Hz), 7.62 (1H, s), 7.90 (1H, d, J=3.6Hz), 8.30 (1H, d, J=2.8 Hz), 8.35 (1H, d, J=8.8 Hz), 8.68 (1H, d, J=5.2Hz), 8.79 (1H, s).

The intermediates were synthesized in the following manner.

Production Example 287-14-(1H-Indol-5-yloxy)-7-(2-methoxyethoxy)quinoline-6-carbonitrile

The title compound (0.8 g) was obtained as a solid from4-chloro-7-methoxyethoxy-6-cyanoquinoline (1.0 g) and 5-hydroxyindole,in the same manner as Example 309.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.37 (3H, s), 3.76-3.79 (2H, m),4.39-4.43 (2H, m), 6.43 (1H, d, J=5.6 Hz), 6.45-6.49 (1H, m), 6.99 (1H,dd, J=2.4 Hz, J=8.8 Hz), 7.43-7.47 (2H, m), 7.52 (1H, d, J=8.8 Hz), 7.61(1H, s), 8.66 (1H, d, J=5.6 Hz), 8.79 (1H, s), 11.31 (1H, br s).

Example 2884-(1H-Indol-5-yloxy)-7-(3-(pyrrolidin-1-yl)propoxy)quinoline-6-carbonitrile

The title compound (1.27 g) was obtained as a solid from4-(1H-Indol-5-yloxy)-7-hydroxyquinoline-6-carbonitrile (1.98 g) and1-(3-chloropropyl)pyrrolidine hydrochloride, in the same manner asExample 7.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.64-1.72 (4H, m), 1.95-2.03 (2H, m),2.42-2.48 (4H, m), 2.59 (2H, t, J=7.2 Hz), 4.32 (2H, t, J=6.4 Hz), 6.43(1H, d, J=5.2 Hz), 6.46-6.48 (1H, m), 6.99 (1H, dd, J=2.4 Hz, J=8.8 Hz),7.43-7.47 (2H, m), 7.51 (1H, d, J=8.8 Hz), 7.57 (1H, s), 8.66 (1H, d,J=5.2 Hz), 8.78 (1H, s), 11.30 (1H, br s).

Example 2895-[6-Cyano-7-(3-(pyrrolidin-1-yl)propoxy)quinolin-4-yloxy]indole-1-carboxylicacid (thiazol-2-yl)amide

The title compound (155 mg) was obtained as a solid from4-(1H-indol-5-yloxy)-7-(3-(pyrrolidin-1-yl)propoxy)quinoline-6-carbonitrile(200 mg), in the same manner as Example 312.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.66-1.76 (4H, m), 1.98-2.07 (2H, m),2.52-2.61 (4H, m), 2.70 (2H, t, J=7.2 Hz), 4.34 (2H, t, J=6.4 Hz), 6.51(1H, d, J=5.2 Hz), 6.63 (1H, d, J=3.6 Hz), 6.95 (1H, d, J=4.4 Hz), 7.16(1H, dd, J=2.4 Hz, J=8.8 Hz), 7.38 (1H, d, J=4.4 Hz), 7.50 (1H, d, J=2.4Hz), 7.59 (1H, s), 8.09 (1H, d, J=3.6 Hz), 8.68 (1H, d, J=5.2 Hz), 8.72(1H, d, J=8.8 Hz), 8.81 (1H, s).

Example 2905-[6-Cyano-7-(2-methoxyethoxy)quinolin-4-yloxy]indole-1-carboxylic acid(thiazol-2-yl)amide

The title compound (31 mg) was obtained as a solid from4-(1H-indol-5-yloxy)-7-(2-methoxyethoxy)quinoline-6-carbonitrile (100mg), in the same manner as Example 312.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.37 (3H, s), 3.77-3.80 (2H, m), 4.41(2H, m), 6.51 (1H, d, J=5.2 Hz), 6.59-6.64 (1H, m), 6.88-6.95 (1H, m),7.12-7.18 (1H, m), 7.32-7.39 (1H, m), 7.48-7.51 (1H, m), 7.62 (1H, s),8.06-8.13 (1H, m), 8.69 (1H, d, J=5.2 Hz), 8.69-8.77 (1H, m), 8.81 (1H,s).

Example 291 5-(7-Benzyloxy-6-cyanoquinolin-4-yloxy]indole-1-carboxylicacid (2-fluoroethyl)-amide

The title compound (3.6 g) was obtained as a solid from5-(7-benzyloxy-6-cyanoquinolin-4-yloxy)indole (4.5 g) and(2-fluoroethyl)carbamic acid phenyl ester, in the same manner as Example310.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.54-3.61 (1H, m), 3.61-3.66 (1H, m),4.53 (1H, t, J=4.8 Hz), 4.65 (1H, t, J=4.8 Hz), 5.45 (2H, s), 6.48 (1H,d, J=5.2 Hz), 6.73 (1H, d, J=3.6 Hz), 7.20 (1H, dd, J=2.4 Hz, J=8.8 Hz),7.34-7.39 (1H, m), 7.42-7.47 (2H, m), 7.53-7.57 (3H, m), 7.70 (1H, s),7.98 (1H, d, J=3.6 Hz), 8.36 (1H, d, J=8.8 Hz), 8.50 (1H, t, J=5.2 Hz),8.68 (1H, d. J=5.2 Hz), 8.82 (1H, s).

Example 292 5-(6-Cyano-7-hydroxyquinolin-4-yloxy]indole-1-carboxylicacid (2-fluoroethyl)amide

The title compound (2.17 g) was obtained as a solid from5-(7-benzyloxy-6-cyanoquinolin-4-yloxy]indole-1-carboxylic acid(2-fluoroethyl)amide (3 g) using trifluoroacetic acid, by the sameprocedure as in Production Example 21.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.54-3.59 (1H, m), 3.61-3.65 (1H, m),4.53 (1H, t, J=5.2 Hz), 4.65 (1H, t, J=5.2 Hz), 6.39 (1H, d, J=5.2 Hz),6.73 (1H, d, J=3.6 Hz), 7.19 (1H, dd, J=2.4 Hz, J=8.8 Hz), 7.41 (1H, s),7.53 (1H, d, J=2.4 Hz), 7.98 (1H, d, J=3.6 Hz), 8.35 (1H, d, J=8.8 Hz),8.50 (1H, t, J=5.2 Hz), 8.61 (1H, d. J=5.2 Hz), 8.71 (1H, s).

Example 2935-[6-Cyano-7-(piperidin-4-yl)methoxy)quinolin-4-yloxy]indole-1-carboxylicacid (2-fluoroethyl)amide

In the same manner as Example 301, a tert-butoxycarbonyl compound (150mg) was obtained from5-(6-cyano-7-hydroxyquinolin-4-yloxy]indole-1-carboxylic acid(2-fluoroethyl)amide (1 g) and 4-bromoethylpiperidine-1-carboxylic acidtert-butyl ester, and then the tert-butoxycarbonyl group was deprotectedwith trifluoroacetic acid to obtain the title compound (97 mg) as asolid.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.48-1.61 (2H, m), 1.95-2.02 (2H, m),2.16-2.26 (1H, m), 2.92-3.01 (2H, m), 3.28-3.38 (2H, m), 3.54-3.59 (1H,m), 3.61-3.66 (1H, m), 4.02-4.07 (1H, m), 4.22 (2H, d, J=6.4 Hz), 4.53(1H, t, J=5.2 Hz), 4.65 (1H, t, J=5.2 Hz), 6.49 (1H, d, J=5.2 Hz), 6.74(1H, d, J=4.0 Hz), 7.19 (1H, dd, J=2.4 Hz, J=8.8 HZ), 7.54 (1H, d, J=2.4Hz), 7.64 (1H, s), 7.99 (1H, d, J=4.0 Hz), 8.36 (1H, d, J=8.8 Hz), 8.51(1H, t, J=5.6 Hz), 8.82 (1H, s).

Example 2945-[6-Cyano-7-(1-(methylpiperidin-4-yl)methoxy)quinolinyloxy]indole-1-carboxylicacid (2-fluoroethyl)amide

The title compound (35 mg) was obtained as a solid from5-[6-cyano-7-(piperidin-4-ylmethoxy)quinolinyloxy]indole-1-carboxylicacid (2-fluoroethyl)amide (97 mg), in the same manner as Example 302.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.52-1.61 (2H, m), 1.89-2.07 (5H, m),2.31 (3H, s), 2.92-2.98 (2H, m), 3.69-3.74 (1H, m), 3.76-3.81 (1H, m),4.30 (2H, d, J=6.0 Hz), 4.68 (1H, t, J=5.2 Hz), 4.80 (1H, t, J=5.2 Hz),6.63 (1H, d, J=5.2 Hz), 6.88 (1H, d, J=4.0 Hz), 7.35 (1H, dd, J=2.4 Hz,J=8.8 Hz), 7.69 (1H, d, J=2.4 Hz), 7.73 (1H, s), 8.13 (1H, d, J=4.0 Hz),8.51 (1H, d, J=8.8 Hz), 8.65 (1H, t, J=5.2 Hz), 8.83 (1H, d, J=5.2 Hz),8.94 (1H, s).

Example 2955-[6-Cyano-7-(2-methoxyethoxy)quinolin-4-yloxy]indole-1-carboxylic acidethylamide

The title compound (77 mg) was obtained as a solid from7-(methoxyethoxy)-4-(1H-indol-5-yloxy)quinoline-6-carbonitrile (100 mg),in the same manner as Example 310.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.18 (3H, t, J=7.2 Hz), 3.28-3.33(2H, m), 3.37 (1H, s), 3.76-3.80 (2H, m), 4.40-4.44 (2H, m), 6.48 (1H,d, J=5.2 Hz), 6.71 (1H, d, J=3.6 Hz), 7.19 (1H, dd, J=2.4 Hz, J=8.8 Hz),7.53 (1H, d, J=2.4 Hz), 7.62 (1H, s), 7.93 (1H, d, J=3.6 Hz), 8.24 (1H,d, J=5.2 Hz), 8.35 (1H, d, J=8.8 Hz), 8.69 (1H, d, J=5.2 Hz), 8.80 (1H,s).

Example 2967-(3-Diethylaminopropoxy)-4-(1H-indol-5-yloxy)quinoline-6-carbonitrile

The title compound (0.46 g) was obtained as a solid from4-(1H-indol-5-yloxy)-7-hydroxyquinoline-6-carbonitrile (0.8 g) and3-diethylaminopropyl chloride, in the same manner as Example 7.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.95 (6H, t, J=7.2 Hz), 1.88-1.94(2H, m), 2.43-2.49 (4H, m), 2.59 (2H, t, J=6.8 Hz), 4.30 (2H, t, J=6.0Hz), 6.42 (1H, d, J=5.2 Hz), 6.45-6.48 (1H, m), 6.98 (1H, dd, J=2.4 Hz,J=8.8 Hz), 7.43-7.47 (2H, m), 7.51 (1H, d, J=8.8 Hz), 7.55 (1H, s), 8.65(1H, d, J=5.2 Hz), 8.77 (1H, s), 11.30 (1H, br s).

Example 2975-[6-Cyano-7-(3-diethylaminopropoxy)quinolin-4-yloxy]indole-1-carboxylicacid ethylamide

The title compound (35 mg) was obtained as a solid from7-(3-diethylaminopropoxy)-4-(1H-indol-5-yloxy)quinoline-6-carbonitrile(230 mg), in the same manner as Example 310.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.95 (6H, t, J=7.2 Hz), 1.18 (3H, t,J=7.2 Hz), 1.89-1.94 (2H, m), 2.43-2.49 (4H, m), 2.59 (2H, t, J=7.2 Hz),3.29-3.37 (2H, m), 4.31 (2H, t, J=6.0 Hz), 6.47 (1H, d, J=5.2 Hz), 6.70(1H, d, J=3.6 Hz), 7.18 (1H, dd, J=2.4 Hz, J=8.8 Hz), 7.52 (1H, d, J=2.4Hz), 7.57 (1H, s), 7.93 (1H, d, J=3.6 Hz), 8.24 (1H, t, J=5.2 Hz), 8.35(1H, d, J=8.8 Hz), 8.67 (1H, d, J=5.2 Hz), 8.78 (1H, s).

Example 2985-[6-Cyano-7-(3-diethylaminopropoxy)quinolin-4-yloxy]indole-1-carboxylicacid cyclopropylamide

The title compound (0.21 g) was obtained as a solid from7-(3-diethylaminopropoxy)-4-(1H-indol-5-yloxy)quinoline-6-carbonitrile(0.5 g), in the same manner as Example 310.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.59-0.64 (2H, m), 0.71-0.76 (2H, m),0.95 (6H, t, J=7.2 Hz), 1.87-1.95 (2H, m), 2.43-2.49 (4H, m), 2.59 (2H,t, J=6.8 Hz), 2.74-2.81 (1H, m), 4.31 (2H, t, J=6.0 Hz), 6.46 (1H, d,J=5.2 Hz), 6.68 (1H, d, J=3.6 Hz), 7.19 (1H, dd, J=2.4 Hz, J=8.8 Hz),7.52 (1H, d, J=2.4 Hz), 7.56 (1H, s), 7.90 (1H, d, J=3.6 Hz), 8.30 (1H,d, J=3.2 Hz), 8.35 (1H, d, J=8.8 Hz), 8.67 (1H, d, J=5.2 Hz), 8.78 (1H,s).

Example 2995-[6-Cyano-7-(3-(pyrrolidin-1-yl)propoxy)quinolin-4-yloxy]indole-1-carboxylicacid ethylamide

The title compound (31 mg) was obtained as a solid from7-(3-(pyrrolidin-1-yl)propoxy)-4-(1H-indol-5-yloxy)quinoline-6-carbonitrile(100 mg), in the same manner as Example 310.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.18 (3H, t, J=7.2 Hz), 1.85-1.99(4H, m), 2.40-2.49 (2H, m), 3.01-3.48 (8H, m), 4.39 (2H, t, J=6.0 Hz),6.50 (1H, d, J=5.2 Hz), 6.71 (1H, d, J=3.6 Hz), 7.18 (1H, dd, J=2.4 Hz,J=8.8 Hz), 7.53 (1H, d, J=2.4 Hz), 7.62 (1H, s), 7.96 (1H, d, J=3.6 Hz),8.28 (1H, t, J=5.2 Hz), 8.36 (1H, d, J=8.8 Hz), 8.70 (1H, d, J=5.2 Hz),8.82 (1H, s).

Example 3005-[6-Cyano-7-(3-diethylaminopropoxy)quinolin-4-yloxy]indole-1-carboxylicacid (thiazol-2-yl)amide

The title compound (5 mg) was obtained as a solid from7-(3-diethylaminopropoxy)-4-(1H-indol-5-yloxy)quinoline-6-carbonitrile(80 mg), in the same manner as Example 312.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.00 (6H, t, J=7.2 Hz), 1.93-2.01(2H, m), 2.59 (4H, q, J=7.2 Hz), 2.72 (2H, t, J=6.8 Hz), 4.33 (2H, t,J=6.0 Hz), 6.51 (1H, d, J=5.2 Hz), 6.64 (1H, d, J=3.6 Hz), 6.98 (1H, d,J=4.0 Hz), 7.16 (1H, dd, J=2.4 Hz, J=8.8 Hz), 7.40 (1H, d, J=4.0 Hz),7.50 (1H, d, J=2.4 Hz), 7.58 (1H, s), 8.09 (1H, d, J=3.6 Hz), 8.68 (1H,d, J=5.2 Hz), 8.70 (1H, d, J=8.8 Hz), 8.81 (1H, s).

Example 3016-Cyano-4-(1H-indol-5-yloxy)-7-(piperidin-4-yl)methyloxyquinoline

6-Cyano-4-(1H-indol-5-yloxy)-7-[(1-(t-butoxycarbonyloxy)piperidin-4-yl)methyloxy]quinoline(0.25 g, 0.5015 mmol) was dissolved in ethanol (2 ml) andtetrahydrofuran (2 ml), and then concentrated hydrochloric acid (0.2 ml)was added at room temperature and the mixture was stirred for 17 hours.The solvent was distilled off under reduced pressure, saturated sodiumbicarnobate water was added, and then extraction was performed with atetrahydrofuran and ethyl acetate mixed solvent, the extract was washedwith saturated brine and dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure. The residue wasadsorbed onto NH silica gel and purified by column chromatography (ethylacetate-methanol system) with NH silica gel, and the obtained crystalswere suspended in ethanol and diluted with diethyl ether and hexane. Thecrystals were filtered out, washed with diethyl ether and dried byaspiration to obtain the title compound (15 mg, 0.0376 mmol, 7.51%).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.23-1.29 (2H, m), 1.74-1.77 (2H, m),1.95 (1H, brs), 2.48-2.55 (2H, m), 2.97-3.00 (2H, m), 4.12 (2H, d, J=5.6Hz), 6.43 (1H, d, J=5.2 Hz), 6.47 (1H, s), 6.88 (1H, dd, J=2.4, 9.2 Hz),7.45 (1H, d, J=2.4 Hz), 7.46 (1H, s), 7.52 (1H, d, J=9.2 Hz), 7.57 (1H,s), 8.66 (1H, d, J=5.2 Hz), 8.79 (1H, s), 11.31 (1H, s).

The starting materials were synthesized in the following manner.

Production Example 301-17-Benzyloxy-6-cyano-4-(1H-indol-5-yloxy)quinoline

After suspending 7-benzyloxy-6-cyano-4-chloroquinoline (23 g, 78.03mmol) in N-methylpyrrolidone (15.8 ml), there were added 5-hydroxyindole(12.5 g, 83.64 mmol) and diisopropylethylamine (15.8 ml) and the mixturewas heated and stirred at 150° C. for 10 hours. After allowing it tocool to room temperature, water and tetrahydrofuran were added and thecrystals were thoroughly dissolved. After extraction withtetrahydrofuran, washing with saturated brine, drying over anhydrousmagnesium sulfate and distilling off of the solvent, the residue wasadsorbed onto silica gel. Purification was performed by silica gelcolumn chromatography (hexane/tetrahydrofuran system), and thenconcentrated hydrochloric acid (0.2 ml) was added at room temperatureand the mixture was stirred for 17 hours. The solvent was distilled offunder reduced pressure, saturated sodium bicarnobate water was added,and then extraction was performed with a tetrahydrofuran and ethylacetate mixed solvent, the extract was washed with saturated brine anddried over anhydrous magnesium sulfate, and the solvent was distilledoff under reduced pressure. The obtained crystals were suspended inethyl acetate and diluted with diethyl ether and hexane. The crystalswere filtered out, washed with diethyl ether/hexane and dried byaspiration to obtain the title compound (12.5 g, 31.93 mmol, 40.92%) aslight yellow crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 5.45 (2H, s), 6.44 (1H, d, J=5.2 Hz),6.47 (1H, m), 6.99 (1H, dd, J=2.4, 8.8 Hz), 7.37 (1H, t, J=7.4 Hz),7.42-7.46 (4H, m), 7.51-7.56 (3H, m), 7.69 (1H, s), 8.66 (1H, d, J=5.2Hz), 8.82 (1H, s), 11.29 (1H, s).

Production Example 301-2 6-Cyano-4-(1H-indol-5-yloxy)-7-hydroxyquinoline

After dissolving 7-benzyloxy-6-cyano-4-(1H-indol-5-yloxy)quinoline (3 g,7.6642 mmol) in tetrahydrofuran (250 ml), 10% palladium carbon powder(500 mg, wet) was added and the mixture was stirred for 11 hours at roomtemperature under a hydrogen atmosphere. After further adding 10%palladium carbon powder (300 mg, wet) and stirring the mixture for 9hours at room temperature under a hydrogen atmosphere, additional 10%palladium carbon powder (200 mg, wet) was added and the mixture wasstirred for 5 hours at room temperature under a hydrogen atmosphere. Thesolvent was distilled off, washing was performed with ethanol, and thenthe filtrate was distilled off under reduced pressure. The obtainedcrystals were suspended in ethanol and diluted with hexane, and thecrystals were filtered out, washed with hexane:ethanol=3:1 and dried byaspiration to obtain the title compound (1.82 g, 6.0402 mmol, 79.12%) aslight yellow crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 6.34 (1H, d, J=5.4 Hz), 6.46 (1H, m),6.98 (1H, dd, J=2.4, 8.8 Hz), 7.40-7.46 (3H, m), 7.51 (1H, d, J=8.8 Hz),8.58 (1H, d, J=5.4 Hz), 8.70 (1H, s), 11.29 (1H, s), 11.58 (1H, s).

Production Example 301-36-Cyano-4-(1H-indol-5-yloxy)-7-[(1-(tert-butoxycarbonyloxy)piperidin-4-yl)methyloxy]quinoline

After dissolving 6-cyano-4-(1H-indol-5-yloxy)-7-hydroxyquinoline (1.72g, 5.7084 mmol) in N,N-dimethylformamide (20 ml), there were addedpotassium carbonate (0.87 g, 6.2792 mmol) and tert-butyl4-bromomethylpiperidine-1-carboxylate (1.75 g, 6.2792 mmol), and themixture was heated and stirred at 70° C. for 7 hours. After allowing itto cool to room temperature, water was added, extraction was performedwith ethyl acetate and tetrahydrofuran, the extract was washed withsaturated brine and dried over anhydrous magnesium sulfate and thesolvent was distilled off under reduced pressure, after which theresidue was adsorbed onto silica gel. Purification was performed bysilica gel column chromatography (hexane/ethyl acetate system), and thenethyl acetate/ethanol/hexane was added to the obtained yellow oil toprecipitate crystals. The crystals were filtered out, washed withhexane:ethanol=10:1 and dried by aspiration to obtain the title compound(1.786 g, 3.3852 mmol, 59.30%) as light yellow crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.20-1.33 (2H, m), 1.39 (9H, s),1.78-1.82 (2H, m), 2.06 (1H, m), 2.78 (2H, m), 3.98-4.02 (2H, n), 4.17(2H, d, J=6.4 Hz), 6.43 (1H, d, J=5.2 Hz), 6.49 (1H, s), 6.98 (1H, dd,J=2.4 Hz, 8.8 Hz), 7.44-7.46 (2H, m), 7.51 (1H, d, J=8.8 Hz), 7.58 (1H,s), 8.66 (1H, d, J=5.2 Hz), 8.79 (1H, s), 11.30 (1H, s).

Example 3026-Cyano-4-(1H-indol-5-yloxy)-7-[(1-methylpiperidin-4-yl)methyloxy]quinoline

After dissolving6-cyano-4-(1H-indol-5-yloxy)-7-[(1-methylpiperidin-4-yl)methyloxy]quinoline(30 mg, 0.0753 mmol) in tetrahydrofuran (2.5 ml) and methanol (2.5 ml),there were added acetic acid (0.009 ml) and an aqueous formalin solution(0.047 ml, 0.5648 mmol, 12N). Sodium cyanoborohydride (10 mg) was addedat room temperature, and the mixture was stirred at room temperature for1 hour. Saturated sodium bicarnobate water was added, extraction wasperformed with ethyl acetate and tetrahydrofuran, the extract was washedwith saturated brine and dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure, after which theresidue was adsorbed onto NH silica gel. Purification was then performedby NH silica gel column chromatography (ethyl acetate:methanol=10:1),and the obtained crystals were suspended in diethyl ether. The crystalswere filtered out and dried by aspiration to obtain the title compound(7 mg, 0.0170 mmol, 22.54%) as colorless crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.35-1.44 (2H, m), 1.76-1.91 (5H, m),2.15 (3H, s), 2.78-2.82 (2H, m), 4.14 (2H, d, J=6.0 Hz), 6.42 (1H, d,J=5.2 Hz), 6.47 (1H, s), 6.98 (1H, dd, J=2.4, 8.8 Hz), 7.44-7.46 (2H,m), 7.51 (1H, d, J=8.8 Hz), 7.57 (1H, s), 8.66 (1H, d, J=5.2 Hz), 8.78(1H, s), 11.31 (1H, s).

Example 3036-Cyano-4-(1-ethylcarbamoylindol-5-yloxy)-7-[(piperidin-4-yl)methyloxy]quinoline

After dissolving6-cyano-4-(1-ethylcarbamoylindol-5-yloxy)-7-[(1-(t-butoxycarbonyloxy)piperidin-4-yl)methyloxy]quinoline(180 mg, 0.0753 mmol) in trifluoroacetic acid (1 ml), the solution wasstirred at room temperature for 0.5 hour. Saturated sodium bicarnobatewater was added, extraction was performed with ethyl acetate andtetrahydrofuran, the extract was washed with saturated brine and driedover anhydrous magnesium sulfate, and the solvent was distilled offunder reduced pressure, after which ethanol was added to the obtainedamorphous substance for crystallization. After dilution with hexane, thecrystals were filtered out, washed with hexane and dried by aspirationto obtain the title compound (132 mg, 0.2811 mmol, 88.96%) as colorlesscrystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.18 (3H, t, J=7.2 Hz), 1.50-1.59(2H, m), 1.96-2.01 (2H, m), 2.21 (1H, brs), 2.93-2.99 (2H, m), 3.28-3.37(4H, m), 4.22 (2H, d, J=6.0 Hz), 6.49 (1H, d, J=5.6 Hz), 6.71 (1H, d,J=3.6 Hz), 7.17 (1H, dd, J=2.4, 8.8 Hz), 7.53 (1H, d, J=2.4 Hz), 7.64(1H, s), 7.95 (1H, d, J=8.8 Hz), 8.26 (1H, t, J=5.4 Hz), 8.36 (1H, d,J=8.8 Hz), 8.42 (1H, brs), 8.69 (1H, d, J=5.6 Hz), 8.81 (1H, s).

The starting material was synthesized in the following manner.

Production Example 303-16-Cyano-4-(1-ethylcarbamoylindol-5-yloxy)-7-[(1-(t-butoxycarbonyloxy)piperidin-4-yl)methyloxy]quinoline

The title compound (180 mg, 0.3160 mmol, 44.74%) was obtained ascolorless crystals by reaction in the same manner as Example 310, using6-cyano-4-(1H-indol-5-yloxy)-7-[(1-(t-butoxycarbonyloxy)piperidin-4-yl)methyloxy]quinoline(350 mg, 0.7062 mmol) and phenyl N-ethylcarbamate (140 mg).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.18 (3H, t, J=7.0 Hz), 1.18-1.35(2H, m), 1.40 (9H, s), 1.78-1.82 (2H, m), 2.16 (1H, m), 2.79 (2H, m),3.32 (2H, q, J=7.0 Hz), 3.98-4.02 (2H, m), 4.18 (2H, d, J=6.0 Hz), 6.48(1H, d, J=5.2 Hz), 6.70 (1H, d, J=3.8 Hz), 7.18 (1H, dd, J=2.4, 9.2 Hz),7.52 (1H, d, J=2.4 Hz), 7.59 (1H, s), 7.93 (1H, d, J=3.8 Hz), 8.22 (1H,brs), 8.35 (1H, d, J=9.2 Hz), 8.68 (1H, d, J=5.2 Hz), 8.79 (1H, s).

Example 3046-Cyano-4-(1-ethylcarbamoylindol-5-yloxy)-7-[(1-methylpiperidin-4-yl)methyloxy]quinoline

After reaction in the same manner as Example 302 using6-cyano-4-(1-ethylcarbamoylindol-5-yloxy)-7-[(piperidin-4-yl)methyloxy]quinoline(122 mg, 0.2598 mmol), the product was purified by NH silica gel columnchromatography (ethyl acetate-methanol=10:1). The obtained crystals weresuspended in ethanol and diluted with hexane, and the crystals werefiltered out and dried by aspiration to obtain the title compound (28mg, 0.0579 mmol, 22.29%) as colorless crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.20 (3H, t, J=7.2 Hz), 1.38-1.47(2H, m), 1.78-1.93 (5H, m), 2.18 (3H, s), 2.80-2.84 (2H, m), 3.33-3.37(2H, m), 4.17 (2H, d, J=6.0 Hz), 6.49 (1H, d, J=5.2 Hz), 6.72 (1H, d,J=3.6 Hz), 7.20 (1H, dd, J=2.4, 9.2 Hz), 7.54 (1H, d, J=2.4 Hz), 7.60(1H, s), 7.95 (1H, d, J=3.6 Hz), 8.25 (1H, m), 8.37 (1H, d, J=9.0 Hz),8.70 (1H, d, J=5.2 Hz), 8.80 (1H, s).

Example 3056-Cyano-4-(1-cyclopropylcarbamoylindol-5-yloxy)-7-[(piperidin-4-yl)methyloxy]quinoline

The title compound (962 mg, quant.) was obtained using6-cyano-4-(1-cyclopropylcarbamoylindol-5-yloxy)-7-[(1-(t-butoxycarbonyloxy)piperidin-4-yl)methyloxy]quinoline(965 mg, 1.6590 mmol), in the same manner as Example 301.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.60-0.64 (2H, m), 0.71-0.74 (2H, m),1.50-1.60 (2H, m), 1.96-2.00 (2H, m), 2.21 (1H, m), 2.75-2.81 (1H, m),2.90-2.98 (2H, m), 3.28-3.36 (2H, m), 4.21 (2H, d, J=6.0 Hz), 6.49 (1H,d, J=5.2 Hz), 6.69 (1H, d, J=3.8 Hz), 7.19 (1H, dd, J=2.4 Hz, 8.8 Hz),7.52 (1H, d, J=2.4 Hz), 7.64 (1H, s), 7.92 (1H, d, J=3.8 Hz), 8.33 (1H,m), 8.36 (1H, d, J=8.8 Hz), 8.51 (1H, brs), 8.69 (1H, d, J=5.2 Hz), 8.81(1H, s).

The starting material was synthesized in the following manner.

Production Example 305-16-Cyano-4-(1-cyclopropylcarbamoylindol-5-yloxy)-7-[(1-(t-butoxycarbonyloxy)piperidin-4-yl)methyloxy]quinoline

The title compound (965 mg, 1.6590 mmol, 82.72%) was obtained as lightred crystals by reaction in the same manner as Example 310, using6-cyano-4-(1H-indol-5-yloxy)-7-[(1-(t-butoxycarbonyloxy)piperidin-4-yl)methyloxy]quinoline(1.0 g, 2.0056 mmol) and phenyl N-cyclopropylcarbamate (426 mg).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.59-0.64 (2H, m), 0.71-0.76 (2H, m),1.21-1.33 (2H, m), 1.40 (9H, s), 1.78-1.82 (2H, m), 2.07 (1H, m),2.40-2.70 (3H, m), 3.95-4.15 (2H, m), 4.18 (2H, d, J=6.0 Hz), 6.48 (1H,d, J=5.2 Hz), 6.80 (1H, d, J=3.6 Hz), 7.19 (1H, dd, J=2.4 Hz, 8.8 Hz),7.52 (1H, d, J=2.4 Hz), 7.59 (1H, s), 7.90 (1H, d, J=3.6 Hz), 8.29 (1H,brs), 8.35 (1H, d, J=8.8 Hz), 8.68 (1H, d, J=5.2 Hz), 8.79 (1H, s).

Example 3066-Cyano-4-(1-cyclopropylcarbamoylindol-5-yloxy)-7-[(1-methylpiperidin-4-yl)methyloxy]quinoline

The title compound (335 mg, 0.6760 mmol, 37.76%) was obtained ascolorless crystals using6-cyano-4-(1-cyclopropylcarbamoylindol-5-yloxy)-7-[(piperidin-4-yl)methyloxy]quinoline(862 mg, 1.7900 mmol), by the same procedure as in Example 320.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.59-0.64 (2H, m), 0.71-0.76 (2H, m),1.35-1.45 (2H, m), 1.76-1.91 (5H, m), 2.16 (3H, s), 2.74-2.82 (3H, m),4.15 (2H, d, J=6.0 Hz), 6.47 (1H, d, J=5.2 Hz), 6.68 (1H, d, J=3.8 Hz),7.19 (1H, dd, J=2.4 Hz, 8.8 Hz), 7.52 (1H, d, J=2.4 Hz), 7.58 (1H, s),7.90 (1H, d, J=3.8 Hz), 8.30 (1H, d, J=2.4 Hz), 8.35 (1H, d, J=8.8 Hz),8.68 (1H, d, J=5.2 Hz), 8.78 (1H, s).

Example 3076-Cyano-7-[(piperidin-4-yl)methyloxy]-4-[1-(2-thiazolylcarbamoyl)indol-5-yloxy]quinoline

The title compound (114 mg, 0.2136 mmol) was obtained as colorlesscrystals using6-cyano-4-[1-(2-thiazolylcarbamoyl)indol-5-yloxy]-7-[(1-(t-butoxycarbonyloxy)piperidin-4-yl)methyloxy]quinoline(220 mg, 0.3522 mmol), in the same manner as Example 301.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.50-1.60 (2H, m), 1.97-2.01 (2H, m),2.22 (1H, brs), 2.93-2.99 (2H, m), 3.31-3.37 (2H, m), 4.22 (2H, d, J=5.6Hz), 6.53 (1H, d, J=5.2 Hz), 6.70 (1H, d, J=3.0 Hz), 7.09 (1H, d, J=4.2Hz), 7.20 (1H, dd, J=2.4 Hz, 8.8 Hz), 7.47 (1H, d, J=4.2 Hz), 7.53 (1H,d, J=2.4 Hz), 7.65 (1H, s), 8.09 (1H, d, J=3.0 Hz), 8.10-8.67 (1H, brs),8.67 (1H, d, J=8.8 Hz), 8.70 (1H, d, J=5.2 Hz), 8.83 (1H, s).

The starting material was synthesized in the following manner.

Production Example 307-16-Cyano-4-[1-(2-thiazolylcarbamoyl)indol-5-yloxy]-7-[(1-(t-butoxycarbonyloxy)piperidin-4-yl)methyloxy]quinoline

The title compound (220 mg, 0.3522 mmol, 58.53%) was obtained as lightyellow crystals by reaction in the same manner as Example 312, using6-cyano-4-(1H-indol-5-yloxy)-7-[(1-(t-butoxycarbonyloxy)piperidin-4-yl)methyloxy]quinoline(300 mg, 0.6017 mmol), sodium hydride (51 mg, 1.2636 mmol, 60% in oil)and phenyl N-(2-thiazolyl)carbamate (146 mg, 0.6619 mmol).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.21-1.33 (2H, m), 1.39 (9H, s),1.78-1.82 (2H, m), 2.06 (1H, m), 2.78 (2H, m), 3.98-4.02 (2H, m), 4.17(2H, d, J=6.4 Hz), 6.51 (1H, d, J=5.2 Hz), 6.69 (1H, d, J=3.4 Hz), 7.08(1H, d, J=4.6 Hz), 7.20 (1H, dd, J=2.4 Hz, 9.2 Hz), 7.47 (1H, d, J=4.6Hz), 7.53 (1H, d, J=2.4 Hz), 7.59 (1H, s), 8.08 (1H, d, J=3.4 Hz), 8.67(1H, d, J=9.2 Hz), 8.69 (1H, d, J=5.2 Hz), 8.80 (1H, s).

Example 3086-Cyano-7-[(1-methylpiperidin-4-yl)methyloxy]-4-[1-(2-thiazolylcarbamoyl)indol-5-yloxy]quinoline

The same reaction was conducted as in Example 302 using6-cyano-7-[(piperidin-4-yl)methyloxy]-4-[1-(2-thiazolylcarbamoyl)indol-5-yloxy]quinoline(104 mg, 0.1982 mmol), the product was purified by NH silica gel columnchromatography (ethyl acetate:methanol=10:1), the obtained crystals weresuspended in ethanol and diluted with hexane, and the crystals werefiltered out and dried by aspiration to obtain the title compound (38mg, 0.0705 mmol, 35.60%) as colorless crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.45-1.48 (2H, m), 1.83-1.95 (3H, m),2.08-2.15 (2H, m), 2.29 (3H, s), 2.93-2.96 (2H, m), 4.19 (2H, d, J=5.6Hz), 6.53 (1H, d, J=5.2 Hz), 6.67 (1H, d, J=3.4 Hz), 7.01 (1H, d, J=4.4Hz), 7.19 (1H, dd, J=2.4 Hz, 9.2 Hz), 7.42 (1H, d, J=4.4 Hz), 7.53 (1H,d, J=2.4 Hz), 7.62 (1H, s), 7.81 (1H, d, J=3.4 Hz), 8.71 (1H, d, J=5.2Hz), 8.73 (1H, d, J=9.2 Hz), 8.83 (1H, s).

Example 309 6-Carbamoyl-4-(1H-indol-5-yloxy)-7-methoxyquinoline

After mixing 6-carbamoyl-4-chloro-7-methoxyquinoline (2.0 g, 8.4509mmol), 5-hydroxyindole (1.68 g), diisopropylethylamine (2.2 ml) andN-methylpyrrolidone (2.2 ml), the mixture was heated and stirred at 150°C. for 5 hours. After cooling, the partly solidified reaction mixturewas dissolved in dimethylsulfoxide and then adsorbed onto NH silica geland purified by NH silica gel column chromatography (ethylacetate-methanol system). The obtained crystals were suspended inethanol, the suspension was diluted with diethyl ether and hexane, andthe crystals were filtered out, washed with diethyl ether:hexane=1:5 anddried by aspiration to obtain the title compound (1.291 g, 3.8698 mmol,45.79%) as light yellow crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 4.02 (3H, s), 6.37 (1H, d, J=5.2 Hz),6.46 (1H, brs), 6.98 (1H, dd, J=2.4 Hz, 8.4 Hz), 7.43-7.45 (2H, m), 7.48(1H, s), 7.51 (1H, d, J=8.4 Hz), 7.71 (1H, brs), 7.84 (1H, brs), 8.58(1H, d, J=5.2 Hz), 8.74 (1H, s), 11.29 (1H, s).

Example 3106-Carbamoyl-4-[1-(2,4-difluorophenylcarbamoyl)1H-indol-5-yloxy]-7-methoxyquinoline

After dissolving 6-carbamoyl-4-(1H-indol-5-yloxy)-7-methoxyquinoline(100 mg, 0.3 mmol) in N,N-dimethylformamide (0.5 ml), there was addedsodium hydride (12 mg, 0.3 mmol) while cooling on ice and the mixturewas stirred at room temperature for 15 minutes. After adding phenylN-(2,4-difluorophenyl)carbamate (79 mg, 0.3150 mmol), the mixture wasstirred at room temperature for 2 hours. Water was added to the reactionsolution, extraction was performed with ethyl acetate andtetrahydrofuran, the extract was washed with saturated brine and driedover anhydrous magnesium sulfate, and the filtrate was distilled offunder reduced pressure. The obtained crystals were suspended in ethanoland diluted with hexane, and then the crystals were filtered out, washedwith hexane and dried by aspiration to obtain the title compound (84 mg,0.1718 mmol, 57.28%) as colorless crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 4.03 (3H, s), 6.45 (1H, J, J=5.2 Hz),6.81 (1H, d, J=3.8 Hz), 7.14-7.19 (1H, m), 7.23 (1H, dd, J=2.4 Hz, 8.8Hz), 7.39-7.49 (1H, m), 7.51 (1H, s), 7.50-7.58 (2H, m), 7.72 (1H, brs),7.85 (1H, brs), 8.11 (1H, d, J=3.8 Hz), 8.32 (1H, d, J=8.8 Hz), 8.62(1H, d, J=5.2 Hz), 8.73 (1H, s), 10.03 (1H, s).

The starting material was synthesized in the following manner.

Production Example 310-1 Phenyl N-(2,4-difluorophenyl)carbamate

After dissolving 2,4-difluoroaniline (10 ml, 98.21 mmol) intetrahydrofuran (200 ml), pyridine (8.7 ml, 108.33 mmol) was added atroom temperature and the mixture was stirred. It was then cooled on ice,phenyl chloroformate (13.6 ml, 108.33 mmol) was added dropwise over 15minutes, and the mixture was then stirred at room temperature for 24hours. Water was added to the reaction solution, extraction wasperformed with ethyl acetate and tetrahydrofuran, the extract was washedwith saturated brine and dried over anhydrous magnesium sulfate, and thefiltrate was distilled off under reduced pressure. The obtained crystalswere suspended in ethanol and diluted with hexane, and then the crystalswere filtered out, washed with hexane and dried by aspiration to obtainthe title compound (21.00 g, 84.26 mmol, 85.80%) as light violetcrystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 7.05-7.12 (1H, m), 7.19 (2H, d, J=7.6Hz), 7.24 (1H, t, J=7.6 Hz), 7.33 (1H, m), 7.41 (2H, t, J=7.6 Hz),7.59-7.68 (1H, m), 9.91 (1H, brs).

Example 3116-Carbamoyl-4-[1-(4-difluorophenylcarbamoyl)1H-indol-5-yloxy]-7-methoxyquinoline

The title compound (60 mg, 0.1275 mmol, 42.51%) was obtained ascolorless crystals by reaction in the same manner as Example 310, using6-carbamoyl-4-(1H-indol-5-yloxy)-7-methoxyquinoline (100 mg, 0.3 mmol)and phenyl N-(4-fluorophenyl)carbamate (86 mg).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 4.03 (3H, s), 6.45 (1H, d, J=5.2 Hz),6.79 (1H, d, J=3.6 Hz), 7.21-7.26 (3H, m), 7.51 (1H, s), 7.57 (1H, d,J=2.0 Hz), 7.67 (2H, dd, J=5.2 Hz, 8.8 Hz), 7.73 (1H, brs), 7.85 (1H,brs), 8.13 (1H, d, J=3.6 Hz), 8.33 (1H, d, J=8.8 Hz), 8.62 (1H, d, J=5.2Hz), 8.73 (1H, s), 10.16 (1H, s).

The starting material was synthesized in the following manner.

Production Example 311-1 Phenyl N-(4-difluorophenyl)carbamate

The title compound (10.031 g, 43.38 mmol, 82.19%) was obtained as lightviolet crystals using 4-fluoroaniline (5 ml, 52.78 mmol), by the sameprocedure as in Production Example 310-1.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 7.13-7.27 (5H, m), 7.39-7.44 (2H, m),7.48-7.52 (2H, m), 10.26 (1H, s).

Example 3126-Carbamoyl-4-[1-(2-thiazolylcarbamoyl)1H-indol-5-yloxy]-7-methoxyquinoline

After suspending sodium hydride (50 mg, 1.2524 mmol) inN,N-dimethylformamide (0.5 ml), phenyl N-(2,4-difluorophenyl)carbamate(79 mg, 0.3150 mmol) and then6-carbamoyl-4-(1H-indol-5-yloxy)-7-methoxyquinoline (200 mg, 0.5964mmol) were added thereto at room temperature, and the mixture wasstirred at room temperature for 10 hours. Water and saturated brine wereadded to the reaction solution, extraction was performed with ethylacetate and tetrahydrofuran, the extract was washed with saturated brineand dried over anhydrous magnesium sulfate, and the filtrate wasdistilled off under reduced pressure. The residue was adsorbed ontosilica gel and passed through a silica gel column(hexane-tetrahydrofuran system). The obtained crystals were wetted withone drop of dimethylsulfoxide and then suspended in ethanol, and thecrystals were filtered out, washed with ethanol and dried by aspirationto obtain the title compound (138 mg, 0.3003 mmol, 50.36%) as lightyellow crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 4.03 (3H, s), 6.46 (1H, d, J=5.2 Hz),6.69 (1H, d, J=3.6 Hz), 7.09 (1H, d, J=4.4

Hz), 7.20 (1H, dd, J=2.4 Hz, 8.8 Hz), 7.47 (1H, d, J=4.4 Hz), 7.51 (1H,s), 7.52 (1H, d, J=2.4 Hz), 7.73 (1H, brs), 7.86 (1H, brs), 8.08 (1H, d,J=3.6 Hz), 8.62 (1H, d, J=5.2 Hz), 8.67 (1H, d, J=8.8 Hz), 8.74 (1H, s),13.16 (1H, s).

Example 3136-Carbamoyl-4-(1-cyclopropylcarbamoyl-1H-indol-5-yloxy)-7-methoxyquinoline

The title compound (35 mg, 0.0840 mmol, 28.02%) was obtained ascolorless crystals by reaction in the same manner as Example 310, using6-carbamoyl-4-(1H-indol-5-yloxy)-7-methoxyquinoline (100 g, 0.3 mmol)and phenyl N-(4-fluorophenyl)carbamate (56 mg).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.62 (2H, m), 0.73 (2H, m), 2.78 (1H,m), 4.02 (3H, s), 6.42 (1H, d, J=5.2 Hz), 6.68 (1H, d, J=3.2 Hz), 7.18(1H, d, J=9.0 Hz), 7.50 (2H, m), 7.73 (1H, s), 7.85 (1H, s), 7.89 (1H,d, J=3.2 Hz), 8.30 (1H, s), 8.34 (1H, d, J=9.0 Hz), 8.61 (1H, d, J=5.2Hz), 8.72 (1H, s).

The starting material was synthesized in the following manner.

Production Example 313-1 Phenyl N-cyclopropylcarbamate

Cyclopropylamine (3 ml, 43.29 mmol) was used for reaction in the samemanner as Production Example 310-1, the obtained crystals were suspendedin diethyl ether:hexane=1:2, and the crystals were then filtered out,washed with diethyl ether:hexane=1:2 and dried by aspiration to obtainthe title compound (5.832 g, 32.91 mmol, 76.03%) as light yellowcrystals

¹H-NMR Spectrum (CDCl13) δ (ppm): 0.60-0.65 (2H, m), 0.76-0.80 (2H, m),2.69 (1H, brs), 5.23 (1H, brs), 7.13 (2H, d, J=7.6 Hz), 7.19 (1H, t,J=7.6 Hz), 7.35 (2H, t, J=7.6 Hz).

Example 3146-Carbamoyl-4-[1-(2-fluoroethylcarbamoyl)1H-indol-5-yloxy]-7-methoxyquinolineExample 3154-[1-(2-Fluoroethylcarbamoyl)1H-indol-5-yloxy]-6-(2-fluoroethylureidocarbamoyl)-7-methoxyquinoline

6-Carbamoyl-4-(1H-indol-5-yloxy)-7-methoxyquinoline (800 mg, 2.3998mmol), sodium hydride (104 mg, 2.5918 mmol) and phenylN-(2-fluoroethyl)carbamate (483 mg, 2.6398 mmol) were used for reactionin the same manner as Example 310, extraction was performed with ethylacetate and tetrahydrofuran, the extract was washed with saturated brineand dried over anhydrous magnesium sulfate, and the solvent wasdistilled off under reduced pressure. The residue was adsorbed ontosilica gel and subjected to silica gel column chromatography (ethylacetate-tetrahydrofuran-methanol system), and after removing off thestarting materials, the product was adsorbed onto NH silica gel andsubjected to NH silica gel column chromatography (ethylacetate-tetrahydrofuran-methanol system) to obtain low polarity and highpolarity compounds as crystals. These were each suspended in ethanol anddiluted with hexane. The crystals were filtered out, washed with hexaneand dried by aspiration, to obtain the low polarity compound4-[1-(2-fluoroethylcarbamoyl)-1H-indol-5-yloxy]-6-(2-fluoroethylureidocarbamoyl)-7-methoxyquinoline(49 mg, 0.0958 mmol, 3.99%) as colorless crystals and the high polaritycompound6-carbamoyl-4-[1-(2-fluoroethylcarbamoyl)1H-indol-5-yloxy]-7-methoxyquinoline(632 mg, 1.4961 mmol, 62.34%) as light yellow crystals.

Low polarity compound (Example 315)

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.59 (4H, m), 4.01 (3H, s), 4.47 (1H,m), 4.53 (1H, m), 4.59 (1H, m), 4.65 (1H, m), 6.46 (1H, d, J=4.4 Hz),6.73 (1H, d, J=2.0 Hz), 7.19 (1H, d, J=8.8 Hz), 7.53 (2H, s), 7.97 (1H,d, J=2.0 Hz), 8.35 (1H, d, J=8.8 Hz), 8.50 (1H, m), 8.51 (1H, s), 8.63(1H, m), 8.64 (1H, d, J=4.4 Hz), 10.62 (1H, s).

High polarity compound (Example 314)

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.56 (1H, dt, J=5.0 Hz, 5.0 Hz), 3.63(1H, dt, J=5.0 Hz, 5.0 Hz), 4.02 (3H, s), 4.53 (1H, t, J=5.0 Hz), 4.65(1H, t, J=5.0 Hz), 6.43 (1H, d, J=5.2 Hz), 6.73 (1H, d, J=3.8 Hz), 7.19(1H, dd, J=2.4 Hz, 8.8 Hz), 7.50 (1H, s), 7.52 (1H, d, J=2.4 Hz), 7.72(1H, brs), 7.85 (1H, brs), 7.98 (1H, d, J=3.8 Hz), 8.35 (1H, d, J=8.8Hz), 8.49 (1H, t, J=5.0 Hz), 8.61 (1H, d, J=5.2 Hz), 8.72 (1H, s).

The starting material was synthesized in the following manner.

Production Example 314-1 Phenyl N-(2-fluoroethyl)carbamate

After dissolving 2-fluoroethylamine (0.5 g, 5.0321 mmol) indimethylformamide (10 ml), pyridine (0.87 ml, 10.5674 mmol) was added atroom temperature and the mixture was stirred. It was then cooled on ice,phenyl chloroformate (0.67 ml, 5.2837 mmol) was added dropwise, andafter the dropwise addition the mixture was stirred at room temperaturefor 2.5 hours. Water was added to the reaction solution, extraction wasperformed with ethyl acetate, the extract was washed with saturatedbrine and dried over anhydrous magnesium sulfate, and the solvent wasdistilled off under reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=2:1) to obtain the titlecompound (0.797 g, 4.3509 mmol, 86.46%) as light yellow crystals.

¹H-NMR Spectrum (CDCl3) δ (ppm): 3.55 (1H, q, J=4.8 Hz), 3.62 (1H, q,J=4.8 Hz), 4.51 (1H, t, J=4.8 Hz), 4.62 (1H, t, J=4.8 Hz), 5.39 (1H,brs), 7.13 (2H, d, J=7.6 Hz), 7.21 (1H, t, J=7.6 Hz), 7.37 (2H, t, J=7.6Hz).

Example 3166-Carbamoyl-4-(1-ethylcarbamoyl-1H-indol-5-yloxy)-7-methoxyquinolineExample 3174-(1-Ethylcarbamoyl-1H-indol-5-yloxy)-6-ethylureidocarbamoyl-7-methoxyquinoline

6-Carbamoyl-4-(1H-indol-5-yloxy)-7-methoxyquinoline (1.2 g, 3.6141mmol), phenyl N-4-ethylcarbamate (822 mg, 4.9761 mmol) and sodiumhydride (195 mg, 4.8799 mmol) were used for reaction in the same manneras Example 310 to obtain the low polarity compound4-(1-ethylcarbamoyl-1H-indol-5-yloxy)-6-ethylureidocarbamoyl-7-methoxyquinoline(105 mg, 0.2208 mmol, 6.11%) and the high polarity compound6-carbamoyl-4-(1-ethylcarbamoyl-1H-indol-5-yloxy)-7-methoxyquinoline(506 mg, 1.2511 mmol, 34.62%), both as colorless crystals.

Low polarity compound (Example 317)

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.11 (3H, t, J=7.2 Hz), 1.77 (3H, t,J=7.2 Hz), 3.23 (2H, q, J=7.2 Hz), 3.29 (2H, q, J=7.2 Hz), 4.01 (3H, s),6.45 (1H, d, J=5.2 Hz), 6.70 (1H, d, J=3.6 Hz), 7.17 (1H, dd, J=2.4 Hz,8.8 Hz), 7.51 (1H, d, J=2.4 Hz), 7.52 (1H, s), 7.93 (1H, d, J=3.6 Hz),8.24 (1H, t, J=5.6 Hz), 8.35 (1H, d, J=8.8 Hz), 8.44 (1H, m), 8.52 (1H,s), 8.64 (1H, d, J=5.2 Hz), 10.46 (1H, s).

High polarity compound (Example 316)

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.18 (3H, t, J=7.2 Hz), 3.32 (2H, q,J=7.2 Hz), 4.02 (3H, s), 6.42 (1H, d, J=5.2 Hz), 6.70 (1H, d, J=3.6 Hz),7.17 (1H, dd, J=2.4 Hz, 8.8 Hz), 7.50 (1H, s), 7.51 (1H, d, J=2.4 Hz),7.71 (1H, brs), 7.84 (1H, brs), 7.93 (1H, d, J=3.6 Hz), 8.23 (1H, t,J=5.6 Hz), 8.34 (1H, d, J=8.8 Hz), 8.61 (1H, d, J=5.2 Hz), 8.72 (1H, s).

The starting material was synthesized in the following manner.

Production Example 316-1 Phenyl N-ethyl carbamate

Ethylamine hydrochloride (20.3 g, 0.25 mol) was used for reaction in thesame manner as Production Example 310-1, the obtained crystals weresuspended in hexane, and then the crystals were filtered out, washedwith hexane and dried by aspiration to obtain the title compound (33.33g, 0.2018 mol, 80.71%) as colorless crystals.

¹H-NMR Spectrum (CDCl3) δ (ppm): 1.21 (3H, t, J=7.2 Hz), 3.31 (2H, m),5.02 (1H, brs), 7.12 (2H, d, J=7.6 Hz), 7.19 (1H, t, J=7.6 Hz), 7.35(2H, t, J=7.6 Hz).

Example 3186-Carbamoyl-7-methoxy-4-(1-propylcarbamoyl-1H-indol-5-yloxy)quinolineExample 3197-Methoxy-4-(1-propylcarbamoyl-1H-indol-5-yloxy)-6-propylureidocarbamoylquinoline

6-Carbamoyl-4-(1H-indol-5-yloxy)-7-methoxyquinoline (400 mg, 1.2 mmol),phenyl N-n-propyl carbamate (237 mg, 1.3199 mmol) and sodium hydride (55mg, 1.3199 mmol) were used according to the same method as in Example310 to obtain the low polarity compound7-methoxy-4-(1-propylcarbamoyl-1H-indol-5-yloxy)-6-propylureidocarbamoylquinoline(49 mg, 0.0973 mmol, 8.11%) and the high polarity compound6-carbamoyl-7-methoxy-4-(1-normalpropylcarbamoyl-1H-indol-5-yloxy)quinoline(218 mg, 0.5210 mmol, 43.41%), both as light yellow crystals.

Low polarity compound (Example 319)

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.89 (3H, t, J=7.2 Hz), 0.91 (3H, t,J=7.2 Hz), 1.51 (2H, q, J=7.2 Hz), 1.59 (2H, q, J=7.2 Hz), 3.18 (2H, t,J=7.2 Hz), 3.25 (2H, t, J=7.2 Hz), 4.02 (3H, s), 6.45 (1H, d, J=5.2 Hz),6.70 (1H, d, J=3.6 Hz), 7.27 (1H, dd. J=2.4 Hz, 8.8 Hz), 7.51 (1H, d,J=2.4 Hz), 7.52 (1H, s) 7.95 (1H, d, J=3.6 Hz), 8.22 (1H, m), 8.34 (1H,d, J=8.8 Hz), 8.47 (1H, brs), 8.54 (1H, s), 8.64 (1H, d, J=5.2 Hz),10.45 (1H, s).

High polarity compound (Example 318)

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.92 (3H. t, J=7.2 Hz), 1.58 (2H, q,J=7.2 Hz), 3.24 (2H, q, J=7.2 Hz), 4.02 (3H, s), 6.42 (1H, d, J=5.2 Hz),6.70 (1H, d, J=3.6 Hz), 7.17 (1H, dd, J=2.4 Hz, 8.8 Hz), 7.50 (1H, s),7.51 (1H, d, J=2.4 Hz), 7.72 (1H, brs), 7.49 (1H, brs), 7.95 (1H, d,J=3.6 Hz), 8.23 (1H, t, J=5.2 Hz), 8.34 (1H, d, J=8.8 Hz), 8.61 (1H, d,J=5.2 Hz), 8.72 (1H, s).

The starting material was synthesized in the following manner.

Production Example 318-1 Phenyl N-(n-propyl)carbamate

n-Propylamine (4.1 ml, 50 mmol) was used for reaction in the same manneras Production Example 310-1, and the obtained crystals were suspended inhexane, filtered out, washed with hexane and dried by aspiration toobtain the title compound (4.502 g, 25.12 mmol, 50.24%) as colorlesscrystals

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.86 (3H, t, J=7.4 Hz), 1.41-1.50(2H, m), 3.00 (2H, q, J=6.8 Hz), 7.06 (2H, d, J=8.0 Hz), 7.17 (1H, t,J=8.0 Hz), 7.36 (2H, t, J=8.0 Hz), 7.72 (1H, m).

Example 3206-Carbamoyl-7-methoxy-4-[1-(1-methyl)ethylcarbamoyl-1H-indol-5-yloxy]quinolineExample 3217-Methoxy-4-[1-(1-methyl)ethylcarbamoyl-1H-indol-5-yloxy]-6-(1-methyl)ethylureidocarbamoylquinoline

6-Carbamoyl-4-(1H-indol-5-yloxy)-7-methoxyquinoline (400 mg, 1.2 mmol),phenyl N-(1-methyl)ethyl carbamate (237 mg) and sodium hydride (55 mg,1.3199 mmol) were used by the same procedure as in Example 310 to obtainthe low polarity compound7-methoxy-4-[1-(1-methyl)ethylcarbamoyl-1H-indol-5-yloxy]-6-(1-methyl)ethylureidocarbamoylquinoline(62 mg, 0.1231 mmol, 10.26%) as light yellow crystals and the highpolarity compound6-carbamoyl-7-methoxy-4-[1-(1-methyl)ethylcarbamoyl-1H-indol-5-yloxy]quinoline(309 mg, 0.7384 mmol, 43.41%) as colorless crystals. The title compound(60 mg, 0.1275 mmol, 61.54%) was obtained as colorless crystals.

Low polarity compound (Example 321)

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.17 (6H, d, J=5.8 Hz), 1.22 (6H, d,J=5.8 Hz), 3.88 (1H, m), 4.01 (3H, s), 4.03 (1H, m), 6.45 (1H, d, J=5.4Hz), 6.69 (1H, d, J=3.4 Hz), 7.16 (1H, dd, J=2.4 Hz, 8.6 Hz), 7.50 (1H,d, J=2.4 Hz), 7.52 (1H, s), 7.98 (1H, s), 7.99 (1H, d, J=3.4 Hz), 8.33(2H, m), 8.52 (1H, s), 8.64 (1H, d, J=5.4 Hz), 10.46 (1H, s).

High polarity compound (Example 320)

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.23 (6H, d, J=6.4 Hz), 4.00 (1H, m),4.33 (3H, s), 6.42 (1H, d, J=5.4 Hz), 6.69 (1H, d, J=3.6 Hz), 7.17 (1H,dd, J=2.4 Hz, 8.8 Hz), 7.50 (1H, s), 7.51 (1H, d, J=2.4 Hz), 7.72 (1H,brs), 7.85 (1H, brs), 7.97 (1H, s), 7.99 (1H, d, J=3.5 Hz), 8.33 (1H, d,J=8.8 Hz), 8.61 (1H, d, J=5.4 Hz), 8.72 (1H, s).

The starting material was synthesized in the following manner.

Production Example 320-1 Phenyl N-(iso-propyl)carbamate

i-Propylamine (4.3 ml, 50 mmol) was used for reaction in the same manneras Production Example 310-1, and the obtained crystals were suspended inhexane, filtered out, washed with hexane and dried by aspiration toobtain the title compound (5.105 g, 28.48 mmol, 56.97%) as colorlesscrystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.01 (6H, d, J=6.4 Hz), 3.58-3.67(1H, m), 7.07 (2H, d, J=7.6 Hz), 7.17 (1H, t, J=7.6 Hz), 7.35 (2H, t,J=7.6 Hz), 7.65 (1H, m).

Example 3224-(1-Normalbutylcarbamoyl-1H-indol-5-yloxy)-6-carbamoyl-7-methoxyquinoline

The title compound (203 mg, 0.4694 mmol, 46.94%) was obtained ascolorless crystals using6-carbamoyl-4-(1H-indol-5-yloxy)-7-methoxyquinoline (335 mg, 1.0 mmol),phenyl N-n-butyl carbamate (213 mg, 1.1 mmol) and sodium hydride (44 mg,1.1 mmol), by the same procedure as in Example 310.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.92 (3H, t, J=7.2 Hz), 1.36 (2H, m),1.55 (2H, m), 3.29 (2H, m), 4.02 (3H, s), 6.42 (1H, d, J=5.4 Hz), 6.70(1H, d, J=3.6 Hz), 7.17 (1H, dd, J=2.4 Hz, 8.8 Hz), 7.50-7.52 (2H, m),7.73 (1H, brs), 7.85 (1H, brs), 7.94 (1H, d. J=3.6 Hz), 8.22 (1H, t,J=5.4 Hz), 8.34 (1H, d, J=8.8 Hz), 8.61 (1H, d, J=5.4 Hz), 8.72 (1H, s).

The starting material was synthesized in the following manner.

Production Example 322-1 Phenyl N-(n-butyl)carbamate

n-Butylamine (4.9 ml, 50 mmol) was used for the same reaction as inProduction Example 310-1, and purification was performed by silica gelcolumn chromatography (hexane:ethyl acetate=4:1) to obtain the titlecompound (8.11 g, 41.97 mmol, 71.97%) as a colorless oil.

¹H-NMR Spectrum (CDCl3) δ (ppm): 0.95 (3H, t, J=7.2 Hz), 1.35-1.45 (2H,m), 1.52-1.60 (2H, m), 3.27 (2H, q, J=7.2 Hz), 5.01 (1H, brs), 7.12 (2H,d, J=7.2 Hz), 7.19 (1H, t, J=7.2 Hz), 7.35 (2H, t, J=7.2 Hz).

Example 3236-Carbamoyl-4-[1-(1,1-dimethylethylcarbamoyl)1H-indol-5-yloxy]-7-methoxyquinoline

The title compound (225 mg, 0.5203 mmol, 52.03%) was obtained ascolorless crystals using6-carbamoyl-4-(1H-indol-5-yloxy)-7-methoxyquinoline (335 mg, 1.0 mmol),phenyl N-(1,1-dimethylethyl)carbamate (213 mg, 1.1 mmol) and sodiumhydride (44 mg, 1.1 mmol), by the same procedure as in Example 310.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.42 (9H, s), 4.02 (3H, s), 6.41 (1H,d, J=5.0 Hz), 6.65 (1H, d, J=3.8 Hz), 7.15 (1H, dd, J=2.4 Hz, 9.2 Hz),7.50 (2H, s), 7.63 (1H, s), 7.72 (1H, brs), 7.85 (1H, brs), 7.95 (1H, d,J=3.8 Hz), 8.26 (1H, d, J=9.2 Hz), 8.61 (1H, d, J=5.0 Hz), 8.73 (1H, s).

The starting material was synthesized in the following manner.

Production Example 323-1 Phenyl N-(t-butyl)carbamate

The title compound (3.910 g, 20.23 mmol, 40.46%) was obtained as pinkcrystals using t-butylamine (5.3 ml, 50 mmol), by the same procedure asin Production Example 310-1.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.26 (9H, s), 7.05 (2H, d, J=8.0 Hz),7.16 (1H, t, J=8.0 Hz), 7.35 (2H, t, J=8.0 Hz), 7.53 (1H, s).

Example 3246-Carbamoyl-4-[1-(3-fluoropropylcarbamoyl)1H-indol-5-yloxy]-7-methoxyquinoline

The title compound (105 mg, 0.2406 mmol, 28.82%) was obtained ascolorless crystals using6-carbamoyl-4-(1H-indol-5-yloxy)-7-methoxyquinoline (280 mg, 0.8349mmol), phenyl N-(3-fluoropropyl)carbamate (181 mg, 0.9184 mmol) andsodium hydride (37 mg, 0.9184 mmol), by the same procedure as in Example310.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.89-2.03 (2H, m), 3.39 (2H, m), 4.02(3H, s), 4.49 (1H, t, J=6.0 Hz), 4.61 (1H, d, J=6.0 Hz), 6.42 (1H, d,J=5.2 Hz), 6.71 (1H, d, J=3.6 Hz), 7.18 (1H, dd, J=2.4 Hz, 8.8 Hz), 7.50(1H, s), 7.52 (1H, d, J=2.4 Hz), 7.72 (1H, brs), 7.85 (1H, brs), 7.94(1H, d, J=3.6 Hz), 8.32 (1H, t, J=5.4 Hz), 8.34 (1H, d, J=8.8 Hz), 8.61(1H, d, J=5.2 Hz), 8.72 (1H, s).

The starting material was synthesized in the following manner.

Production Example 324-1 Phenyl N-(3-fluoropropyl)carbamate

3-Fluoropropylamine hydrochloride (0.92 g (wet), 8.10 mmol) was used forreaction in the same manner as Production Example 310-1, andpurification was performed by silica gel column chromatography(hexane/ethyl acetate system) to obtain the title compound (0.470 g,2.3832 mmol, 29.42%) as pink crystals.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.96 (1H, m), 2.03 (1H, m), 3.44 (2H,q, J=6.4 Hz), 4.54 (1H, t, J=5.6 Hz), 4.65 (1H, t, J=5.6 Hz), 5.22 (1H,brs), 7.12 (2H, d, J=7.6 Hz), 7.20 (1H, t, J=7.6 Hz), 7.36 (2H, t, J=7.6Hz).

Example 3256-Carbamoyl-4-[1-(3-chloropropylcarbamoyl)1H-indol-5-yloxy]-7-methoxyquinoline

The title compound (136 mg, 0.3003 mmol, 35.97%) was obtained ascolorless crystals using6-carbamoyl-4-(1H-indol-5-yloxy)-7-methoxyquinoline (280 mg, 0.8349mmol), phenyl N-(3-chloropropyl)carbamate (197 mg, 0.9184 mmol) andsodium hydride (37 mg, 0.9184 mmol), by the same procedure as in Example310.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.03 (2H, q, J=6.4 Hz), 3.42 (2H, q,J=6.4 Hz), 3.74 (2H, t, J=6.4 Hz), 4.02 (3H, s), 6.42 (1H, d, J=5.2 Hz),6.71 (1H, d, J=3.6 Hz), 7.18 (1H, dd, J=2.4 Hz, 8.8 Hz), 7.50 (1H, s),7.52 (1H, d, J=2.4 Hz), 7.72 (1H, brs), 7.85 (1H, brs), 7.94 (1H, d,J=3.6 Hz), 8.30 (1H, d, J=5.4 Hz), 8.34 (1H, d, J=8.8 Hz), 8.61 (1H, d,J=5.2 Hz), 8.72 (1H, s).

The starting material was synthesized in the following manner.

Production Example 325-1 Phenyl N-(3-chloropropyl)carbamate

3-Chloropropylaminehydrochloride (6.5 g, 50 mmol) was used for reactionin the same manner as Production Example 310-1, purification wasperformed by silica gel column chromatography (hexane/ethyl acetatesystem), the obtained crystals were suspended in diethyl ether anddiluted with hexane, and the crystals were filtered out, washed withhexane and dried by aspiration to obtain the title compound (4.316 g,20.20 mmol, 40.40%) as colorless crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.91 (2H, quintet, J=6.0 Hz), 3.18(2H, q, J=6.0 Hz), 3.68 (2H, t, J=6.0 Hz), 7.08 (2H, d, J=8.0 Hz), 7.18(1H, t, J=8.0 Hz), 7.35 (2H, t, J=8.0 Hz), 7.81 (1H, t, J=6.0 Hz).

Example 3266-Carbamoyl-4-[1-(3-ethoxypropylcarbamoyl)1H-indol-5-yloxy]-7-methoxyquinoline

The title compound (103 mg, 0.2227 mmol, 26.67%) was obtained ascolorless crystals using6-carbamoyl-4-(1H-indol-5-yloxy)-7-methoxyquinoline (280 mg, 0.8349mmol), phenyl N-(3-ethoxypropyl)carbamate (197 mg, 0.9184 mmol) andsodium hydride (37 mg, 0.9184 mmol), by the same procedure as in Example310.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.01 (3H, t, J=6.8 Hz), 1.80 (2H, t,J=6.8 Hz), 3.34 (2H, q, J=6.8 Hz), 3.39-3.46 (4H, m), 4.02 (3H, s), 6.24(1H, d, J=5.2 Hz), 6.70 (1H, d, J=3.6 Hz), 7.18 (1H, dd, J=2.4 Hz, 8.8Hz), 7.50 (1H, s), 7.51 (1H, d, J=2.4 Hz), 7.72 (1H, brs), 7.85 (1H,brs), 7.93 (1H, d, J=3.6 Hz), 8.22 (1H, t, J=5.2 Hz), 8.34 (1H, d, J=8.8Hz), 8.61 (1H, d, J=5.2 Hz), 8.72 (1H, s).

The starting material was synthesized in the following manner.

Production Example 326-1 Phenyl N-(3-ethoxypropyl)carbamate

3-Ethoxypropylamine (6.0 ml, 50 mmol) was dissolved in dimethylformamide(100 ml), the reaction was subsequently conducted in the same manner asProduction Example 310-1, and purification was performed by NH silicagel column chromatography (hexane/ethyl acetate system) to obtain thetitle compound (10.76 g, 48.19 mmol, 96.39%) as a light yellow oil.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.22 (3H, t, J=7.0 Hz), 1.85 (2H,quintet, J=6.0 Hz), 3.40 (2H, q, J=6.0 Hz), 3.51 (2H, q, J=7.0 Hz), 3.56(2H, t, J=6.0 Hz), 5.58 (1H, brs), 7.12 (2H, d, J=7.6 Hz), 7.18 (1H, t,J=7.6 Hz), 7.35 (2H, t, J=7.6 Hz).

Example 3276-Carbamoyl-4-[1-(3-diethylaminopropylcarbamoyl)1H-indol-5-yloxy]-7-methoxyquinoline

The title compound (65 mg, 0.1328 mmol, 18.55%) was obtained ascolorless crystals using6-carbamoyl-4-(1H-indol-5-yloxy)-7-methoxyquinoline (240 mg, 0.7157mmol), phenyl N-(3-diethylaminopropyl)carbamate (197 mg, 0.7872 mmol)and sodium hydride (31 mg, 0.7872 mmol), by the same procedure as inExample 310.

¹H-NMR Spectrum (DMSO-d₆) δ (Ppm): 0.94 (6H, t, J=7.2 Hz), 1.69 (2H, m),2.42-2.48 (6H, m), 3.27-3.30 (2H, m), 4.02 (3H, s), 6.42 (1H, d, J=5.4Hz), 6.70 (1H, d, J=3.6 Hz), 7.17 (1H, dd, J=2.4 Hz, 8.8 Hz), 7.50 (1H,s), 7.51 (1H, d, J=2.4 Hz), 7.72 (1H, brs), 7.84 (1H, brs), 7.91 (1H, d,J=3.6 Hz), 8.26 (1H, t, J=5.6 Hz), 8.33 (1H, d, J=8.8 Hz), 8.61 (1H, d,J=5.4 Hz), 8.72 (1H, s).

Production Example 327-1 Phenyl N-(3-diethylaminopropyl)carbamate

3-Diethylaminopropylamine (7.9 ml, 50 mmol) was dissolved indimethylformamide (100 ml), the reaction was subsequently conducted inthe same manner as Production Example 310-1, and purification wasperformed by NH silica gel column chromatography (hexane/ethyl acetatesystem) to obtain the title compound (7.21 g, 28.80 mmol, 57.60%) as alight yellow oil.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.06 (6H, t, J=7.0 Hz), 1.71 (2H,quintet, J=6.0 Hz), 2.49-2.57 (6H, m), 3.36 (2H, q, J=6. Hz), 6.83 (1H,brs), 7.12 (2H, t, J=7.6 Hz), 7.17 (1H, t, J=7.6 Hz), 7.34 (2H, t, J=7.6Hz).

Example 3286-Carbamoyl-7-methoxy-4-[1-(3-methylthiopropyl)1H-indol-5-yloxy]quinoline

The title compound (177 mg, 0.3810 mmol, 45.64%) was obtained ascolorless crystals using6-carbamoyl-4-(1H-indol-5-yloxy)-7-methoxyquinoline (280 mg, 0.8349mmol), phenyl N-(3-methylthiopropyl)carbamate (207 mg, 0.9184 mmol) andsodium hydride (37 mg, 0.9184 mmol), by the same procedure as in Example310.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.84 (2H, tt, J=6.8 Hz, 6.8 Hz), 2.48(3H, s), 2.55 (2H, t, J=6.8 Hz), 3.57 (2H, m), 4.02 (3H, s), 6.42 (1H,d, J=5.0 Hz), 6.70 (1H, d, J=3.4 Hz), 7.18 (1H, d, J=8.8 Hz), 7.50 (1H,s), 7.51 (1H, s), 7.72 (1H, s), 7.85 (1H, s), 7.94 (1H, d, J=3.4 Hz),8.27 (1H, brs), 8.34 (1H, d, J=8.8 Hz), 8.61 (1H, d, J=5.0 Hz), 8.72(1H, s).

Production Example 328-1 Phenyl N-(3-methylthiopropyl)carbamate

3-Methylthiopropylamine (5.5 ml, 50 mmol) was used for reaction in thesame manner as Production Example 310-1, and purification was performedby silica gel column chromatography (hexane/ethyl acetate system) toobtain the title compound (10.486 g, 46.54 mmol, 93.08%) as a yellowoil.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.89 (2H, quintet, J=6.8 Hz), 2.12 (3H,s), 2.58 (2H, t, J=6.8 Hz), 3.38 (2H, q, J=6.8 Hz), 5.21 (1H, brs), 7.12(2H, t, J=7.6 Hz), 7.19 (1H, t, J=7.6 Hz), 7.35 (2H, t, J=7.6 Hz).

Example 3296-Carbamoyl-4-[1-(2-chloroethylcarbamoyl)1H-indol-5-yloxy]-7-methoxyquinoline

The title compound (36 mg, 0.0820 mmol, 9.82%) was obtained as lightyellow crystals using6-carbamoyl-4-(1H-indol-5-yloxy)-7-methoxyquinoline (280 mg, 0.8349mmol), phenyl N-(2-chloroethyl)carbamate (184 mg, 0.9184 mmol) andsodium hydride (37 mg, 0.9184 mmol), by the same procedure as in Example310.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 4.02 (3H, s), 4.03 (2H, t, J=9.2 Hz),4.59 (2H, t, J=9.2 Hz), 6.44 (1H, d, J=5.6 Hz), 6.75 (1H, d, J=3.6 Hz),7.24 (1H, dd, J=2.4 Hz, 8.8 Hz), 7.51 (1H, s), 7.57 (1H, d, J=2.4 Hz),7.72 (1H, brs), 7.76 (1H, d, J=3.6 Hz), 7.85 (1H, brs), 8.38 (1H, d,J=8.8 Hz), 8.62 (1H, d, J=5.6 Hz), 8.72 (1H, s).

Production Example 329-1 Phenyl N-(2-chloroethyl)carbamate

2-Chloroethylamine hydrochloride (5.8 g, 50 mmol) was used for reactionin the same manner as Production Example 310-1, purification wasperformed by silica gel column chromatography (hexane/ethyl acetatesystem), the obtained crystals were suspended in diethyl ether/hexane,and the crystals were filtered out, washed with hexane and dried byaspiration to obtain the title compound (6.088 g, 30.49 mmol, 60.99%) ascolorless crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.38 (2H, q, J=6.0 Hz), 3.66 (2H, t,J=6.0 Hz), 7.09 (2H, t, J=7.6 Hz), 7.19 (1H, t, J=7.6 Hz), 7.36 (2H, t,J=7.6 Hz), 8.01 (1H, t, J=6.0 Hz).

Example 3304-[1-(2,4-Difluorophenylcarbamoyl)-1H-indol-5-yloxy]-6,7-dimethoxyquinoline

After dissolving 4-(1H-indol-5-yloxy)-6,7-dimethoxyquinoline (40 mg,0.1249 mmol, described in WO9717329) in N,N-dimethylformamide (0.7 ml),sodium hydride (10 mg,) was added and the mixture was stirred at roomtemperature for 15 minutes. 2,4-Difluorophenyl isocyanate (0.018 ml,0.1561 mmol) was further added, and the mixture was stirred at roomtemperature for 2 hours. Water was added to the reaction solution,extraction was performed with ethyl acetate, the extract was washed withsaturated brine and dried over anhydrous magnesium sulfate, and thefiltrate was distilled off under reduced pressure. The obtained crystalswere suspended in diethyl ether:ethanol=10:1 and diluted with hexane,and then the crystals were filtered out, washed with diethylether:ethanol=10:1 and dried by aspiration to obtain the title compound(35 mg, 0.0736 mmol, 58.94%) as colorless crystals.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 4.06 (3H, s), 4.07 (3H, s), 6.44 (1H,J, J=5.2 Hz), 6.75 (1H, d, J=4.0 Hz), 6.94-7.20 (2H, m), 7.23 (1H, dd,J=2.4, 8.8 Hz), 7.42-7.48 (3H, m), 7.63 (1H, s), 8.14-8.22 (1H, m), 8.29(1H, d, J=8.8 Hz), 8.47 (1H, d, J=5.2 Hz).

Example 331-14-[1-(Phenylcarbamoyl)-1H-indol-5-yloxy]-6,7-dimethoxyquinoline

4-(1H-Indol-5-yloxy)-6,7-dimethoxyquinoline (25 mg, 0.0780 mmol) andphenyl isocyanate (0.013 ml, 0.117 mmol) were used for reaction in thesame manner as Example 330, the obtained crystals were suspended indiethyl ether:ethanol=10:1, and then the crystals were filtered out,washed with diethyl ether and dried by aspiration to obtain the titlecompound (11 mg, 0.0250 mmol, 32.09%) as colorless crystals.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 4.03 (3H, s), 4.12 (3H, s), 6.45 (1H,m), 6.73 (1H, m), 7.16-7.27 (2H, m), 7.38-7.43 (3H, m), 7.65-7.69 (3H,m), 7.97 (2H, m), 8.08 (1H, m), 8.43 (1H, brs), 8.38 (1H, d, J=8.8 Hz).

Example 331-24-[1-(2-Thiazolylcarbamoyl)-1H-indol-5-yloxy]-6,7-dimethoxyquinoline

After dissolving 4-(1H-indol-5-yloxy)-6,7-dimethoxyquinoline (25 mg,0.0780 mmol) in N,N-dimethylformamide (0.4 ml), sodium hydride (6 mg)was added and the mixture was stirred at room temperature for 15minutes. Phenyl N-(2-thiazolyl)carbamate (30 mg, 0.1362 mmol) wasfurther added and the mixture was stirred at 80° C. for 2 hours. Waterwas added to the reaction solution, extraction was performed with ethylacetate, the extract was washed with saturated brine and dried overanhydrous magnesium sulfate, and the filtrate was distilled off underreduced pressure. The residue was subjected to silica gel columnchromatography (hexane/ethyl acetate/ethanol system), the obtainedcrystals were suspended in ethanol and diluted with hexane, and then thecrystals were filtered out, washed with hexane and dried by aspirationto obtain the title compound (23 mg, 0.0515 mmol, 66.04%) as lightyellow crystals.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 3.94 (6H, s), 6.42 (1H, d, J=5.2 Hz),6.68 (1H, d, J=3.4 Hz), 7.08 (1H, d, J=4.0 Hz), 7.17 (1H, d, J=8.8 Hz),7.38 (1H, s), 7.46-7.48 (2H, m), 7.56 (1H, s), 8.07 (1H, d, J=3.4 Hz),8.43 (1H, d, J=5.2 Hz), 8.65 (1H, d, J=8.8 Hz), 13.13 (1H, brs).

Example 3324-(1-Cyclopropylcarbamoyl-1H-indol-5-yloxy)-6,7-dimethoxyquinoline

The title compound (30 mg, 0.0744 mmol, 47.64%) was obtained as lightred crystals by reaction in the same manner as Example 310, using4-(1H-indol-5-yloxy)-6,7-dimethoxyquinoline (50 mg, 0.1560 mmol), sodiumhydride (8 mg, 0.1873 mmol) and phenyl N-cyclopropylcarbamate (30 mg,0.1716 mmol).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.71 (2H, m), 0.94 (2H, m), 2.91 (1H,m), 4.06 (3H, s), 4.07 (3H, s), 5.79 (1H, brs), 6.41 (1H, d, J=5.2 Hz),6.63 (1H, d, J=3.2 Hz), 7.16 (1H, dd, J=2.4 Hz, 8.8 Hz), 7.26 (1H, s),7.39-7.43 (2H, m), 7.63 (1H, s), 8.26 (1H, d, J=8.8 Hz), 8.45 (1H, d,J=5.2 Hz).

Example 3334-[1-(2-Fluoroethylcarbamoyl)1H-indol-5-yloxy]-6,7-dimethoxyquinoline

4-(1H-Indol-5-yloxy)-6,7-dimethoxyquinoline (75 mg, 0.3122 mmol), sodiumhydride (13 mg, 0.3278 mmol) and phenyl N-(2-fluoroethyl)carbamate (45mg, 0.3278 mmol) were used for reaction in the same manner as Example310, followed by extraction with ethyl acetate/tetrahydrofuran, washingwith saturated brine and drying over anhydrous magnesium sulfate, andthen the solvent was distilled off under reduced pressure. The residuewas adsorbed onto silica gel and subjected to silica gel columnchromatography (hexane/ethyl acetate system) to obtain the titlecompound (24 mg, 0.0586 mmol, 18.78%) as colorless crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.56 (1H, q, J=5.0 Hz), 3.63 (1H, q,J=5.0 Hz), 3.92 (3H, s), 3.96 (3H, s), 4.53 (1H, t, J=5.0 Hz), 4.65 (1H,t, J=5.0 Hz), 6.39 (1H, d, J=5.0 Hz), 6.71 (1H, d, J=3.8 Hz), 7.17 (1H,dd, J=2.0 Hz, 8.8 Hz), 7.40 (1H, s), 7.49 (1H, d, J=2.0 Hz), 7.55 (1H,s), 7.96 (1H, d, J=3.8 Hz), 8.34 (1H, d, J=8.8 Hz), 8.42 (1H, d, J=5.0Hz), 8.48 (1H, t, J=5.0 Hz).

Example 3346,7-Dimethoxy-4-(5-(1-(4-fluorophenylcarbonyl)-indolyl)oxy)quinoline

After dissolving 6,7-dimethoxy-4-(5-indolyloxy)quinoline (25 mg, 0.0780mmol, described in WO9717329, p. 52) in toluene (1.6 ml), 4-fluorophenylisocyanate (22 ml, 0.1951 mmol, 2.5 eqM) was added and the mixture washeated to reflux for 5 hours and 30 minutes under a nitrogen atmosphere.After cooling, the reaction solution was diluted with ethyl acetate,washed with saturated brine and dried over anhydrous magnesium sulfate,the solvent was distilled off under reduced pressure, and the residuewas purified by silica gel column chromatography (hexane/ethyl acetatesystem). The obtained crystals were suspended in ethanol and dilutedwith hexane, and then the crystals were filtered out, washed with hexaneand dried by aspiration to obtain the title compound (18 mg, 0.0393mmol, 50.44%) as colorless crystals.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 4.05 (3H, s), 4.07 (3H, s), 6.43 (1H,d, J=5.6 Hz), 6.72 (1H, d, J=3.4 Hz), 7.12 (2H, t, J=8.8 Hz), 7.22 (1H,dd, J=2.0, 8.8 Hz), 7.43 (3H, m), 7.53 (2H, m), 7.62 (1H, d, J=3.6 Hz),7.63 (1H, s), 8.29 (1H, d, J=8.8 Hz), 8.46 (1H, d, J=5.6 Hz).

Example 3356,7-Dimethoxy-4-[5-(1-(4-fluorophenylcarbamoyl)-indolinyl)oxy]quinoline

6,7-Dimethoxy(4-(5-indolinyloxy)quinoline (20 mg, 0.0620 mmol) was usedfor reaction in the same manner as Example 334 to obtain the titlecompound (18 mg, 0.0392 mmol, 63.19%) as light yellow crystals.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 3.30 (2H, t, J=8.4 Hz), 4.05 (3H, s),4.06 (3H, s), 4.12 (2H, t, J=8.4 Hz), 6.45 (1H, d, J=5.2 Hz), 6.47 (1H,brs), 7.01-7.07 (4H, m), 7.42 (2H, dd, J=9.2, 13.2 Hz), 7.43 (1H, s),7.57 (1H, s), 8.04 (1H, d, J=8.8 Hz), 8.48 (1H, d, J=5.2 Hz).

The intermediate was synthesized in the following manner.

Production Example 335-1 6,7-Dimethoxy-4-(5-indolinyloxy)quinoline

After dissolving 6,7-dimethoxy-4-(5-indolyloxy)quinoline (30 mg, 0.0780mmol, described in WO9717329, p. 52) in trifluoroacetic acid (0.9 ml),triethylsilane (45 ml, 0.2808 mmol, 3.0 eqM) was added while cooling onice, and the mixture was stirred for 4 hours and 30 minutes at roomtemperature under a nitrogen atmosphere. After cooling, the reactionsolution was diluted with ethyl acetate, neutralized with saturatedsodium bicarnobate water, extracted with ethyl acetate, washed withsaturated brine and dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/ethanolsystem) to obtain the title compound (20 mg, 0.0620 mmol, 66.28%) aslight yellow crystals.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 3.08 (2H, t, J=8.4 Hz), 3.65 (2H, t,J=8.4 Hz), 4.06 (6H, s), 6.48 (1H, d, J=5.4 Hz), 6.69 (1H, d, J=8.4 Hz),6.84 (1H, dd, J=1.6, 8.4 Hz), 6.95 (1H, d, J=1.6 Hz), 7.49 (1H, s), 7.60(1H, s), 8.48 (1H, d, J=5.4 Hz).

Example 336N-(4-(6-Cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)-N′-(3-methylthiopropyl)urea

The title compound (35.7 mg, 0.077 mmol, 87.1%) was obtained as whitecrystals from phenylN-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)carbamate (40 mg,0.088 mmol) and 3-(methylthio)propylamine, by the same procedure as inExample 11.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.68 (2H, m), 2.04 (3H, s), 3.16 (2H,m), 3.18-3.35 (2H, m), 3.36 (3H, s), 3.76-3.79 (2H, m), 4.40-4.42 (2H,m), 6.23 (1H, t, J=5.6 Hz), 6.48 (1H, d, J=5.2 Hz), 7.16 (2H, d, J=9.2Hz), 7.52 (2H, d, J=9.2 Hz), 7.61 (1H, s), 8.59 (1H, s), 8.70 (1H, d,J=4.0 Hz), 8.75 (1H, s).

Example 337N-(4-(6-Cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)-N′-(3-methylsulfonylpropyl)urea

The title compound (32.4 mg, 0.065 mmol, 59.2%) was obtained as whitecrystals from phenylN-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)carbamate (50 mg,0.11 mmol) and 3-(methanesulfonyl)propylamine, by the same procedure asin Example 11.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.85 (2H, m), 2.97 (3H, s), 3.11 (2H,m), 3.21 (2H, m), 3.36 (3H, s), 3.77 (2H, m), 4.41 (2H, m), 6.30 (1H,m), 6.48 (1H, d, J=5.6 Hz), 7.16 (2H, d, J=8.8 Hz), 7.53 (2H, d, J=8.8Hz), 7.61 (1H, s), 8.67 (1H, s), 8.70 (1H, d, J=5.2 Hz), 8.75 (1H, s).

Example 338N-(4-(6-Cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)-N′-(methylsulfonyl)urea

After suspending sodium hydride (11 mg, 0.275 mmol) in tetrahydrofuran(8 ml) under a nitrogen atmosphere, methanesulfonylamide (31.4 mg, 0.330mmol) was added while cooling in an ice water bath, and the mixture wasstirred at room temperature for 10 minutes. PhenylN-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)carbamate (50 mg,0.110 mmol) was added and the mixture was stirred at 60° C. for 1 hour.The insoluble portion was filtered off, and after concentration underreduced pressure, tetrahydrofuran-hexane (1:2) was added forcrystallization to obtain the title compound (37.6 mg, 0.082 mmol,75.0%) as gray crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.75 (3H, s), 3.36 (3H, s), 3.77 (2H,m), 4.41 (2H, m), 6.47 (1H, d, J=5.2 Hz), 7.05 (1H, d, J=8.8 Hz), 7.61(2H, d, J=8.8 Hz), 7.64 (1H, s), 8.44 (1H, s), 8.69 (2H, d, J=5.2 Hz),8.75 (1H, s).

Example 339 Methyl4-(4-(((4-fluoroanilino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylate

The title compound (600 mg, 1.3 mmol, 86.8%) was obtained as light browncrystals from 4-(4-aminophenoxy)-7-methoxy-6-methoxycarbonylquinoline(486 mg, 1.5 mmol) and 4-fluorophenyl isocyanate, by the same procedureas in Example 10.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.85 (3H, s), 3.96 (3H, s), 6.46 (1H,d, J=5.2 Hz), 7.12 (2H, m), 7.23 (2H, d, J=8.8 Hz), 7.46 (2H, m), 7.51(1H, s), 7.58 (2H, d, J=8.8 Hz), 8.59 (1H, s), 8.67 (1H, d, J=5.2 Hz),8.73 (1H, s), 8.82 (1H, s).

The starting material was synthesized in the following manner.

Production Example 339-17-Methoxy-6-methoxycarbonyl-4-(4-nitrophenoxy)quinoline

The title compound (1.743 g, 4.91 mmol, 27.2%) was obtained as lightbrown crystals from the 4-chloro-7-methoxy-6-methoxycarbonylquinolinehydrochloride (5.19 g, 18.0 mmol) described in WO0050405, by the sameprocedure as in Production Example 11.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 3.97 (3H, s), 4.07 (3H, s), 6.62 (1H,d, J=5.2 Hz), 7.32 (2H, d, J=9.2 Hz), 7.55 (1H, s), 8.36 (2H, d, J=9.2Hz), 8.69 (1H, s), 8.76 (1H, d, J=5.2 Hz).

Production Example 339-24-(4-Aminophenoxy)-7-methoxy-6-methoxycarbonylquinoline

The title compound (1.053 g, 3.25 mmol, 66.5%) was obtained as lightbrown crystals from7-methoxy-6-methoxycarbonyl-4-(4-nitrophenoxy)quinoline (1.73 g, 4.88mmol), in the same manner as Production Example 10.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 3.97 (3H, s), 4.04 (3H, s), 6.42 (1H,d, J=5.2 Hz), 6.76 (2H, m), 6.98 (2H, m), 7.48 (1H, s), 8.61 (1H, d,J=5.2 Hz), 8.83 (1H, s).

Example 340 Methyl7-methoxy-4-(4-(((1,3-thiazol-2-ylamino)carbonyl)amino)phenoxy)-6-quinolinecarboxylate

The title compound (306 mg, 0.68 mmol, 45.3%) was obtained as lightbrown crystals from4-(4-aminophenoxy)-7-methoxy-6-methoxycarbonylquinoline (486 mg, 1.5mmol) and phenyl N-(1,3-thiazol-2-yl)carbamate, by the same procedure asin Example 131.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.85 (3H, s), 3.97 (3H, s), 6.47 (1H,d, J=5.2 Hz), 7.11 (1H, br), 7.27 (2H, d, J=9.2 Hz), 7.37 (1H, br), 7.52(1H, s), 7.61 (2H, d, J=9.2 Hz), 8.59 (1H, s), 8.67 (1H, d, J=5.2 Hz),9.11 (1H, br), 10.53 (1H, br).

Example 3414-(4-(((4-Fluoroanilino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid

After adding methanol (9 ml) and 2N aqueous sodium hydroxide (3 ml) tomethyl-4-(4-(((4-fluoroanilino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylate (300 mg, 0.65 mmol), the mixture was stirred at roomtemperature for 2 hours and then at 60° C. for 20 minutes. The reactionsolution was cooled to room temperature and 1N hydrochloric acid wasadded for neutralization, after which methanol (6 ml) and water (6 ml)were added, the mixture was stirred overnight, and the precipitatedlight brown crystals were filtered out and dried under reduced pressureto obtain the title compound (227 mg, 0.51 mmol, 78.0%).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.97 (3H, s), 6.49 (1H, d, J=5.2 Hz),7.11 (2H, m), 7.23 (2H, d, J=8.8 Hz), 7.46 (2H, m), 7.49 (1H, s), 7.58(2H, d, J=8.8 Hz), 8.57 (1H, s), 8.67 (1H, d, J=5.2 Hz), 8.75 (1H, s),8.84 (1H, s).

Example 3427-Methoxy-4-(4-(((1,3-thiazol-2-ylamino)carbonyl)amino)phenoxy)-6-quinolinecarboxylicacid

The title compound (243 mg, 0.56 mmol, 95.4%) was obtained as lightbrown crystals from methyl7-methoxy-4-(4-(((1,3-thiazol-2-ylamino)carbonyl)amino)phenoxy)-6-quinolinecarboxylate (263 mg, 0.58 mmol), by the same procedure as in Example341.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 4.00 (3H, s), 6.63 (1H, d, J=5.2 Hz),7.10 (1H, d, J=3.6 Hz), 7.31 (2H, d, J=8.8 Hz), 7.36 (1H, d, J=3.6 Hz),7.57 (1H, s), 7.65 (2H, d, J=8.8 Hz), 8.62 (1H, s), 8.78 (1H, d, J=5.2Hz), 9.64 (1H, s).

Example 343 2-Propyl4-(4-(((4-fluoroanilino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylate

After dissolving4-(4-(((4-fluoroanilino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid (84 mg, 0.19 mmol) in dimethylformamide (1 ml), there were added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (54 mg, 0.28mmol), 1-hydroxy-1H-benzotriazole monohydrate (38 mg, 0.28 mmol),triethylamine (0.079 ml, 0.56 mmol) and 2-propanol (0.15 ml) whilestirring on ice, and the mixture was stirred overnight at roomtemperature. The reaction solution was directly subjected to silica gelcolumn chromatography (eluent—ethyl acetate), the fraction containingthe target substance was concentrated, suspended in ethyl acetate anddiluted with hexane, and the crystals were filtered out and blow-driedto obtain the title compound (15.0 mg, 0.03 mmol, 16%) as whitecrystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.32 (6H, d, J=6.4 Hz), 3.95 (3H, s),5.15 (1H, m), 6.45 (1H, d, J=5.2 Hz), 7.11 (2H, m), 7.23 (2H, d, J=9.2Hz), 7.46 (2H, m), 7.50 (1H, s), 7.58 (2H, d, J=9.2 Hz), 8.48 (1H, s),8.66 (1H, d, J=5.2 Hz), 8.73 (1H, s), 8.82 (1H, s).

Example 344 2-Methoxyethyl4-(4-(((4-fluoroanilino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylate

After dissolving4-(4-(((4-fluoroanilino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid (84 mg, 0.19 mmol) in dimethylformamide (1 ml), there were added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (54 mg, 0.28mmol), 1-hydroxy-1H-benzotriazole monohydrate (38 mg, 0.28 mmol),triethylamine (0.079 ml, 0.56 mmol) and 2-methoxyethanol (0.15 ml) whilestirring on ice, and the mixture was stirred overnight at roomtemperature. The reaction solution was directly subjected to silica gelcolumn chromatography (eluent—ethyl acetate), the fraction containingthe target substance was concentrated, suspended in ethyl acetate anddiluted with hexane, and the crystals were filtered out and blow-driedto obtain the title compound (47.1 mg, 0.093 mmol, 49.6%) as whitecrystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.29 (3H, s), 3.65 (2H, m), 3.96 (3H,s), 4.40 (2H, m), 6.46 (1H, d, J=5.2 Hz), 7.11 (2H, m), 7.24 (2H, d,J=8.8 Hz), 7.46 (2H, m), 7.51 (1H, s), 7.58 (2H, d, J=8.8 Hz), 8.56 (1H,s), 8.67 (1H, d, J=5.2 Hz), 8.73 (1H, s), 8.81 (1H, s).

Example 345 2-Methoxyethyl7-methoxy-4-(4-(((1,3-thiazol-2-ylamino)carbonyl)amino)phenoxy)-6-quinolinecarboxylate

After dissolving7-methoxy-4-(4-(((1,3-thiazol-2-ylamino)carbonyl)amino)phenoxy)-6-quinolinecarboxylicacid (87.3 mg, 0.20 mmol) in dimethylformamide (1 ml), there were added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (58 mg, 0.30mmol), 1-hydroxy-1H-benzotriazole monohydrate (41 mg, 0.30 mmol),triethylamine (0.084 ml, 0.60 mmol) and 2-methoxyethylamine (0.052 ml,0.60 mmol) while stirring on ice, and the mixture was stirred at roomtemperature for 5 hours. The reaction solution was distributed betweenethyl acetate and water, and the organic layer was washed with water anddried over anhydrous magnesium sulfate. After distilling off thesolvent, ethyl acetate and then hexane was added to precipitatecrystals, which were filtered out and dried under reduced pressure toobtain the title compound (24.4 mg, 0.049 mmol, 24.7%) as whitecrystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.29 (3H, s), 3.48 (4H, s), 4.02 (3H,s), 6.47 (1H, d, J=5.2 Hz), 7.11 (1H, br), 7.26 (2H, d, J=8.8 Hz), 7.37(1H, br), 7.51 (1H, s), 7.61 (2H, d, J=8.8 Hz), 8.44 (1H, s), 8.62 (1H,s), 8.65 (1H, d, J=5.2 Hz), 9.11 (1H, s), 10.54 (1H, s).

Example 346N6-Methoxy-7-methoxy-4-(4-(((1,3-thiazol-2-ylamino)carbonyl)amino)phenoxy)-6-quinolinecarboxamide

The title compound (36.1 mg, 0.078 mmol, 61.5%) was obtained as lightyellow crystals from7-methoxy-4-(4-(((1,3-thiazol-2-ylamino)carbonyl)amino)phenoxy)-6-quinolinecarboxylicacid (55 mg, 0.13 mmol) and methoxylamine hydrochloride, by the sameprocedure as in Example 345.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.73 (3H, s), 3.97 (3H, s), 6.47 (1H,d, J=5.2 Hz), 7.11 (1H, br), 7.25 (2H, d, J=8.8 Hz), 7.37 (1H, br), 7.48(1H, s), 7.62 (2H, d, J=8.8 Hz), 8.44 (1H, s), 8.65 (1H, d, J=5.2 Hz),9.11 (1H, s), 11.44 (1H, s).

Example 3474-(4-(2,4-Difluoroanilino)carbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (59.9 mg, 0.13 mmol, 79.8%) was obtained as lightyellow crystals from 4-(4-aminophenoxy)-7-methoxy-6-quinolinecarboxamide(50 mg, 0.16 mmol) and 2,4-difluorophenyl isocyanate, by the sameprocedure as in Example 10.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 4.00 (3H, s), 6.46 (1H, d, J=5.2 Hz),7.03 (1H, m), 7.23 (2H, d, J=8.8 Hz), 7.33 (1H, m), 7.50 (1H, s), 7.58(2H, d, J=8.8 Hz), 7.72 (1H, s), 7.84 (1H, s), 8.07 (1H, m), 8.52 (1H,s), 8.64 (1H, d, J=5.2 Hz), 8.67 (1H, s), 9.16 (1H, s).

The starting material was synthesized in the following manner.

Production Example 347-14-(4-Aminophenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (1.56 g, 5.0 mmol, 43.4%) was obtained as lightyellow crystals from the 4-(4-aminophenoxy)-6-cyano-7-methoxyquinoline(4.76 g, 11.6 mmol) described in Production Example 14, by the sameprocedure as in Example 112.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 4.00 (3H, s), 5.15 (2H, m), 6.39 (1H,d, J=5.2 Hz), 6.65 (2H, d, J=8.8 Hz), 6.92 (2H, d, J=8.8 Hz), 7.46 (1H,s), 7.70 (1H, s), 7.83 (1H, s), 8.60 (1H, d, J=5.2 Hz), 8.66 (1H, s).

Example 3484-(4-(4-Fluoroanilino)carbonyl)-4-methylaminophenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (265 mg, 0.58 mmol, 64.6%) was obtained as whitecrystals from 7-methoxy-4-(4-methylaminophenoxy)-6-quinolinecarboxamide(288 mg, 0.89 mmol) and 4-fluorophenyl isocyanate, by the same procedureas in Example 10.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.29 (3H, s), 4.00 (3H, s), 6.65 (1H,d, J=5.2 Hz), 7.06 (2H, m), 7.32 (2H, d, J=8.8 Hz), 7.41-7.48 (4H, m),7.51 (1H, s), 7.73 (1H, s), 7.85 (1H, s), 8.23 (1H, s), 8.67 (1H, s),8.69 (1H, d, J=5.2 Hz).

The starting material was synthesized in the following manner.

Production Example 348-17-Methoxy-4-(4-methylaminophenoxy)-6-quinolinecarboxamide

After dissolving 4-methylaminophenol (1.04 g, 8.45 mmol) indimethylsulfoxide (10 ml), sodium hydride (290 mg, 8.45 mmol) wasgradually added at room temperature and the mixture was stirred for 20minutes. The 7-methoxy-4-chloro-6-quinolinecarboxamide (1.00 g, 4.23mmol) obtained in Production Example 152-3 was added, and the mixturewas heated at 100° C. for 3 hours while stirring. Upon cooling to roomtemperature, the reaction solution was distributed between ethyl acetateand water, and the organic layer was washed with water and saturatedbrine and dried over anhydrous sodium sulfate. The solvent was distilledoff and subjected to silica gel column chromatography (eluent—ethylacetate), the fraction containing the target substance was concentrated,suspended in ethyl acetate and diluted with hexane, and the crystalswere filtered out and blow-dried to obtain the title compound (815 mg,2.52 mmol, 59.6%) as white crystals.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 2.88 (3H, s), 4.09-4.16 (4H, m), 5.88(1H, br), 6.45 (1H, d, J=5.6 Hz), 6.68 (2H, m), 7.01 (2H, m), 7.51 (1H,s), 7.80 (1H, br), 8.61 (1H, d, J=5.6 Hz), 9.31 (1H, s).

Example 3497-Methoxy-4-(4-((2-thiazolylamino)carbonyl)-4-methylaminophenoxy)-6-quinolinecarboxamide

The title compound (33.0 mg, 0.073 mmol, 47.5%) was obtained as whitecrystals from 6-carbamoyl-7-methoxy-4-(4-methylaminophenoxy)quinoline(50 mg, 0.16 mmol) and phenyl N-(1,3-thiazol-2-yl)carbamate, by the sameprocedure as in Example 131.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.37 (3H, s), 4.02 (3H, s), 6.64 (1H,br), 7.02 (1H, br), 7.30-7.33 (3H, m), 7.47 (2H, d, J=8.8 Hz), 7.51 (1H,s), 7.72 (1H, s), 7.85 (1H, s), 8.67 (1H, s), 8.69 (1H, d, J=5.2 Hz).

Example 3504-(4-(Cyclopropylaminocarbonyl)-4-methylaminophenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (30.0 mg, 0.073 mmol, 49.4%) was obtained as whitecrystals from 4-nitrophenylN-(4-(6-carbamoyl-7-methoxy-4-quinolyl)oxyphenyl)-N-methylcarbamate (73mg, 0.15 mmol) and cyclopropylamine, by the same procedure as in Example11.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.41 (2H, m), 0.54 (2H, m), 2.50 (1H,m), 3.16 (3H, s), 4.03 (3H, s), 6.27 (1H, d, J=2.8 Hz), 6.60 (1H, d,J=5.6 Hz), 7.27 (2H, m), 7.36 (2H, m), 7.52 (1H, s), 7.73 (1H, s), 7.85(1H, s), 8.66 (1H, s), 8.69 (1H, d, J=5.6 Hz).

The starting material was synthesized in the following manner.

Production Example 350-1 4-NitrophenylN-(4-(6-carbamoyl-7-methoxy-4-quinolyl)oxyphenyl)-N-methyl carbamate

The title compound (373 mg, 0.076 mmol, 76.4%) was obtained as lightyellow crystals from6-carbamoyl-7-methoxy-4-(4-methylaminophenoxy)quinoline (323 mg, 1.00mmol) and 4-nitrophenyl chloroformate, by the same procedure as inProduction Example 17.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 3.47 (3H, s), 4.15 (3H, s), 5.89 (1H,br), 6.56 (1H, d, J=5.6 Hz), 7.23-7.45 (6H, m), 7.56 (1H, s), 7.82 (1H,s), 8.27 (2H, d, J=8.8 Hz), 8.69 (1H, d, J=5.6 Hz), 9.29 (1H, s).

Example 3517-Methoxy-4-(4-((3-methylthiopropylamino)carbonyl)-4-methylaminophenoxy)-6-quinolinecarboxamide

The title compound (44.8 mg, 0.099 mmol, 65.9%) was obtained as whitecrystals from 4-nitrophenylN-(4-(6-carbamoyl-7-methoxy-4-quinolyl)oxyphenyl)-N-methylcarbamate (73mg, 0.15 mmol) and 3-(methylthio)propylamine, by the same procedure asin Example 11.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.64 (2H, m), 2.01 (3H, s), 2.42 (2H,m), 3.09 (2H, m), 3.16 (3H, s), 4.01 (3H, s), 6.17 (1H, t, J=5.6 Hz),6.59 (1H, d, J=5.2 Hz), 7.28 (2H, d, J=8.8 Hz), 7.37 (2H, d, J=8.8 Hz),7.50 (1H, s), 7.72 (1H, s), 7.84 (1H, s), 8.65 (1H, s), 8.67 (1H, d,J=5.2 Hz).

Example 3524-(4-((3-Methylsulfonylpropylamino)carbonyl)-4-methylaminophenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (42.7 mg, 0.088 mmol, 58.7%) was obtained as whitecrystals from 4-nitrophenylN-(4-(6-carbamoyl-7-methoxy-4-quinolyl)oxyphenyl)-N-methylcarbamate (73mg, 0.15 mmol) and 3-(methylsulfonyl)propylamine, by the same procedureas in Example 11.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.81 (2H, m), 2.94 (3H, s), 3.06 (2H,m), 3.12 (2H, m), 3.17 (3H, s), 4.01 (3H, s), 6.26 (1H, t, J=5.6 Hz),6.60 (1H, d, J=5.2 Hz), 7.28 (2H, d, J=8.8 Hz), 7.39 (2H, d, J=8.8 Hz),7.51 (1H, s), 7.72 (1H, s), 7.84 (1H, s), 8.65 (1H, s), 8.68 (1H, d,J=5.2 Hz).

Example 3534-(3-Fluoro-4-((3-methylthiopropylamino)carbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (71.1 mg, 0.155 mmol, 77.5%) was obtained as lightbrown crystals from 4-phenylN-(4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2-fluorophenyl)carbamate(89.5 mg, 0.20 mmol) and 3-(methylthio)propylamine, by the sameprocedure as in Example 11.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.69 (2H, m), 2.04 (3H, s), 2.04-2.05(2H, m), 3.17 (2H, m), 4.01 (3H, s), 6.51 (1H, d, J=5.2 Hz), 6.65 (1H,t, J=6.0 Hz), 7.05 (1H, d, J=9.6 Hz), 7.30 (1H, dd, J=2.8, 11.6 Hz),7.49 (1H, s), 7.71 (1H, s), 7.83 (1H, s), 8.21 (1H, m), 8.33 (1H, s),8.64-8.65 (2H, m).

The starting material was synthesized in the following manner.

Production Example 353-1 PhenylN-(4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2-fluorophenyl) carbamate

The title compound (391.5 mg, 0.875 mmol, 38.1%) was obtained as lightyellow crystals from6-carbamoyl-7-methoxy-4-(3-fluoro-4-aminophenoxy)quinoline (752 mg, 2.30mmol), by the same procedure as in Production Example 17.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 4.14 (3H, s), 5.92 (1H, s), 6.52 (1H,d, J=5.6 Hz), 7.02 (2H, m), 7.21-7.31 (4H, m), 7.43 (2H, m), 7.55 (1H,s), 7.81 (1H, s), 8.23 (1H, br), 8.68 (1H, d, J=5.6 Hz), 9.27 (1H, s).

Example 3544-(3-Fluoro-4-((3-methylsulfonylpropylamino)carbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (41.3 mg, 0.084 mmol, 42.1%) was obtained as whitecrystals from 4-phenylN-(4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2-fluorophenyl)carbamate(89.5 mg, 0.20 mmol) and 3-(methylsulfonyl)propylamine, by the sameprocedure as in Example 11.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.85 (2H, m), 2.97 (3H, s), 3.12 (2H,m), 3.21 (2H, m), 4.01 (3H, s), 6.51 (1H, d, J=5.2 Hz), 6.73 (1H, t,J=5.6 Hz), 7.05 (1H, d, J=9.6 Hz), 7.31 (1H, dd, J=2.8, 11.6 Hz), 7.50(1H, s), 7.72 (1H, s), 7.83 (1H, s), 8.20 (1H, m), 8.40 (1H, s),8.64-8.66 (2H, m).

Example 3554-(3-Fluoro-4-((2,2,2-trifluoroethylamino)carbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (47.4 mg, 0.105 mmol, 69.9%) was obtained as lightyellow crystals from phenylN-(4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2-fluorophenyl)carbamate (67mg, 0.15 mmol) and 2,2,2-trifluoroethylamine, by the same procedure asin Example 11.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.96 (2H, m), 4.02 (3H, s), 6.53 (1H,d, J=5.2 Hz), 7.09 (1H, d, J=8.8 Hz), 7.17 (1H, t, J=6.4 Hz), 7.35 (1H,dd, J=2.8, 11.6 Hz), 7.50 (1H, s), 7.72 (1H, s), 7.84 (1H, s), 8.16 (1H,m), 8.51 (1H, s), 8.64-8.67 (2H, m).

Example 3564-(4-((3-Ethoxypropylamino)carbonyl)amino-3-fluorophenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (45.2 mg, 0.099 mmol, 66.0%) was obtained as lightbrown crystals from phenylN-(4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2-fluorophenyl)carbamate (67mg, 0.15 mmol) and 3-ethoxypropylamine, by the same procedure as inExample 11.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.10 (3H, t, J=7.2 Hz), 1.65 (2H, m),3.14 (2H, q, J=7.2 Hz), 3.35-3.44 (4H, m), 4.01 (3H, s), 6.52 (1H, d,J=5.2 Hz), 6.61 (1H, m), 7.05 (1H, d, J=8.8 Hz), 7.31 (1H, dd, J=2.8,11.6 Hz), 7.50 (1H, s), 7.72 (1H, s), 7.84 (1H, s), 8.22 (1H, m), 8.35(1H, s), 8.64-8.67 (2H, m).

Example 3574-(3-Fluoro-4-((2-fluoroethylamino)carbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (23.9 mg, 0.057 mmol, 77.8%) was obtained as lightbrown crystals from phenylN-(4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2-fluorophenyl)carbamate (33mg, 0.074 mmol) and 2-fluoroethylamine hydrochloride, by the sameprocedure as in Example 11.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.08 (2H, m), 4.02 (3H, s), 4.40 (1H,t, J=5.2 Hz), 4.52 (1H, t, J=5.2 Hz), 6.55 (1H, d, J=5.2 Hz), 6.88 (1H,m), 7.08 (1H, d, J=9.2 Hz), 7.33 (1H, dd, J=2.8, 11.6 Hz), 7.51 (1H, s),7.74 (1H, s), 7.85 (1H, s), 8.21 (1H, m), 8.51 (1H, s), 8.65 (1H, s),8.67 (1H, d, J=5.2 Hz).

Example 3584-(4-((3-Chloropropylamino)carbonyl)amino-3-fluorophenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (22.0 mg, 0.049 mmol, 66.8%) was obtained as lightyellow crystals from phenylN-(4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2-fluorophenyl)carbamate (33mg, 0.074 mmol) and 3-chloropropylamine, by the same procedure as inExample 11.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.89 (2H, m), 3.22 (2H, m), 3.68 (2H,m), 4.01 (3H, s), 6.52 (1H, d, J=5.2 Hz), 6.71 (1H, m), 7.06 (1H, d,J=8.8 Hz), 7.31 (1H, dd, J=2.8, 11.6 Hz), 7.50 (1H, s), 7.72 (1H, s),7.84 (1H, s), 8.20 (1H, m), 8.37 (1H, s), 8.64-8.66 (2H, m).

Example 3594-(3-Fluoro-4-((3-fluoropropylamino)carbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (7.9 mg, 0.018 mmol, 12.2%) was obtained as lightyellow crystals from phenylN-(4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2-fluorophenyl)carbamate (67mg, 0.15 mmol) and 3-fluoropropylamine hydrochloride, by the sameprocedure as in Example 11.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.82 (2H, m), 3.20 (2H, m), 4.01 (3H,s), 4.44 (1H, t, J=6.0 Hz), 4.55 (1H, t, J=6.0 Hz), 6.52 (1H, d, J=5.2Hz), 6.69 (1H, m), 7.06 (1H, d, J=8.8 Hz), 7.31 (1H, dd, J=2.8, 11.6Hz), 7.50 (1H, s), 7.72 (1H, s), 7.84 (1H, s), 8.21 (1H, m), 8.38 (1H,s), 8.64-8.66 (2H, m).

Example 3607-(2-Methoxyethoxy)-4-(4-((3-methoxypropylamino)carbonyl)aminophenoxy)-6-quinolinecarboxamide

The title compound (35.2 mg, 0.075 mmol, 71.1%) was obtained as whitecrystals from phenylN-(4-(6-carbamoyl-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)carbamate (50mg, 0.106 mmol) and 3-methoxypropylamine, by the same procedure as inExample 11.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.66 (2H, m), 3.13 (2H, m), 3.23 (3H,s), 3.28-3.34 (2H, m), 3.36 (3H, s), 3.79 (2H, m), 4.40 (2H, m), 6.16(1H, m), 6.43 (1H, d, J=5.6 Hz), 7.15 (2H, d, J=8.8 Hz), 7.51 (2H, d,J=8.8 Hz), 7.54 (1H, s), 7.79 (1H, s), 7.81 (1H, s), 8.60 (1H, s), 8.63(1H, d, J=5.6 Hz), 8.77 (1H, s).

The starting material was synthesized in the following manner.

Production Example 360-14-(4-Aminophenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxamide

The title compound (1.303 g) was obtained as brown crystals from the4-(4-aminophenoxy)-6-cyano-7-(2-methoxyethoxy)quinoline (3.448 g, 9.67mmol) described in Production Example 10, by the same procedure as inExample 112. This was used directly for the following reaction.

Production Example 360-2 4-PhenylN-(4-(6-carbamoyl-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)carbamate

The title compound (1.462 g, 3.09 mmol, 83.7%) was obtained as lightyellow crystals from4-(4-aminophenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxamide (1.303 g,3.69 mmol), by the same procedure as in Production Example 17.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 3.48 (3H, s), 3.89 (2H, m), 4.44 (2H,m), 5.87 (1H, s), 6.50 (1H, d, J=5.6 Hz), 7.16-7.29 (7H, m), 7.42 (2H,m), 7.58 (1H, s), 7.60 (1H, s), 8.10 (1H, s), 8.64 (1H, d, J=5.6 Hz),9.31 (1H, s).

Example 3614-(4-((2-Fluoroethylamino)carbonyl)aminophenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxamide

The title compound (33.1 mg, 0.075 mmol, 74.8%) was obtained as lightbrown crystals from phenylN-(4-(6-carbamoyl-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)carbamate(47.3 mg, 0.10 mmol) and 2-fluoroethylamine hydrochloride, by the sameprocedure as in Example 11.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.26-3.38 (5H, m), 3.79 (2H, m),4.38-4.41 (3H, m), 4.51 (1H, t, J=5.2 Hz), 6.39 (1H, m), 6.43 (1H, d,J=5.2 Hz), 7.17 (2H, d, J=8.8 Hz), 7.50-7.54 (3H, m), 7.79 (1H, s), 7.81(1H, s), 8.63 (1H, d, J=5.2 Hz), 8.71 (1H, s), 8.77 (1H, s).

Example 3624-(4-((3-Fluoropropylamino)carbonyl)aminophenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxamide

The title compound (8.0 mg, 0.018 mmol, 17.5%) was obtained as lightyellow crystals from phenylN-(4-(6-carbamoyl-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)carbamate(47.3 mg, 0.10 mmol) and 3-fluoropropylamine hydrochloride, by the sameprocedure as in Example 11.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.76-1.87 (2H, m), 3.17 (2H, m), 3.36(3H, s), 3.79 (2H, m), 4.38-4.45 (3H, m), 4.55 (1H, m), 6.24 (1H, m),6.43 (1H, d, J=5.2 Hz), 7.16 (2H, d, J=8.8 Hz), 7.51 (2H, d, J=8.8 Hz),7.53 (1H, s), 7.79 (1H, s), 7.81 (1H, s), 8.62-8.64 (2H, m), 8.77 (1H,s).

Example 3634-(3-Fluoro-4-((3-methoxypropylamino)carbonyl)aminophenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxamide

The title compound (37.2 mg, 0.076 mmol, 75.2%) was obtained as whitecrystals from phenylN-(4-(6-carbamoyl-7-(2-methoxyethoxy)-4-quinolyl)oxy-2-fluorophenyl)carbamate(50 mg, 0.102 mmol) and 3-methoxypropylamine, by the same procedure asin Example 11.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.66 (2H, m), 3.16 (2H, m), 3.23 (3H,s), 3.28-3.34 (2H, m), 3.36 (3H, s), 3.79 (2H, m), 4.40 (2H, m), 6.52(1H, d, J=5.6 Hz), 6.62 (1H, m), 7.06 (1H, d, J=11.2 Hz), 7.31 (1H, dd,J=2.8, 11.6 Hz), 7.55 (1H, s), 7.80 (1H, s), 7.81 (1H, s), 8.22 (1H, m),8.36 (1H, s), 8.65 (1H, d, J=5.6 Hz), 8.75 (1H, s).

The starting material was synthesized in the following manner.

Production Example 363-14-(4-Amino-3-fluorophenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxamide

The title compound (991 mg) was obtained as light yellow crystals fromthe 4-(4-amino-3-fluorophenoxy)-6-cyano-7-(2-methoxyethoxy)quinoline(6.368 g, 18.0 mmol) described in Production Example 12, by the sameprocedure as in Example 112. This was used directly for the followingreaction.

Production Example 363-2 PhenylN-(4-(6-carbamoyl-7-(2-methoxyethoxy)-4-quinolyl)oxy-2-fluorophenyl)carbamate

The title compound (1.074 g, 2.19 mmol, 81.9%) was obtained as lightbrown crystals from4-(4-amino-3-fluorophenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxamide(991 mg, 2.67 mmol), by the same procedure as in Production Example 17.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 3.48 (3H, s), 3.90 (2H, m), 4.46 (2H,m), 5.88 (1H, s), 6.58 (1H, d, J=5.2 Hz), 7.02-7.06 (2H, m), 7.21-7.30(4H, m), 7.43 (2H, m), 7.71 (1H, s), 8.08 (1H, s), 8.27 (1H, br), 8.68(1H, d, J=5.2 Hz), 9.29 (1H, s).

Example 3644-(4-(3-Fluoro(2-fluoroethylamino)carbonyl)aminophenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxamide

The title compound (35.4 mg, 0.077 mmol, 76.9%) was obtained as whitecrystals from phenylN-(4-(6-carbamoyl-7-(2-methoxyethoxy)-4-quinolyl)oxy-2-fluorophenyl)carbamate(49.1 mg, 0.10 mmol) and 2-fluoroethylamine hydrochloride, by the sameprocedure as in Example 11.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.36 (3H, s), 3.45 (2H, m), 3.79 (2H,m), 4.38-4.41 (3H, m), 4.52 (1H, t, J=4.8 Hz), 6.52 (1H, d, J=5.2 Hz),6.87 (1H, m), 7.07 (1H, d, J=6.8 Hz), 7.33 (1H, dd, J=2.8, 11.6 Hz),7.55 (1H, s), 7.79 (1H, s), 7.81 (1H, s), 8.20 (1H, m), 8.49 (1H, s),8.65 (1H, d, J=5.2 Hz), 8.75 (1H, s).

Example 3654-(4-(3-Fluoro(2-fluoropropylamino)carbonyl)aminophenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxamide

The title compound (6.8 mg, 0.014 mmol, 14.3%) was obtained as lightyellow crystals from phenylN-(4-(6-carbamoyl-7-(2-methoxyethoxy)-4-quinolyl)oxy-2-fluorophenyl)carbamate(49.1 mg, 0.10 mmol) and 3-fluoropropylamine hydrochloride, by the sameprocedure as in Example 11.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.76-1.87 (2H, m), 3.18 (2H, m), 3.34(3H, s), 3.79 (2H, m), 4.38-4.45 (3H, m), 4.55 (1H, m), 6.52 (1H, d,J=5.2 Hz), 6.69 (1H, m), 7.07 (1H, d, J=8.8 Hz), 7.32 (1H, dd, J=2.8,11.6 Hz), 7.55 (1H, s), 7.80 (1H, s), 7.81 (1H, s), 8.21 (1H, m), 8.39(1H, s), 8.65 (1H, d, J=5.2 Hz), 8.75 (1H, s).

Example 3664-(3-Chloro-4-((4-fluoroanilino)carbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (53.6 mg, 0.111 mmol, 76.9%) was obtained as lightbrown crystals from4-(4-amino-3-chlorophenoxy)-7-methoxy-6-quinolinecarboxamide (50 mg,0.145 mmol) and 4-fluorophenyl isocyanate, by the same procedure as inExample 10.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 4.01 (3H, s), 6.55 (1H, d, J=5.2 Hz),7.14 (2H, m), 7.28 (1H, dd, J=2.4, 9.2 Hz), 7.47 (2H, m), 7.51 (1H, s),7.55 (1H, d, J=2.4 Hz), 7.73 (1H, s), 7.85 (1H, s), 8.25 (1H, d, J=9.2Hz), 8.38 (1H, s), 8.65 (1H, s), 8.67 (1H, d, J=5.2 Hz), 9.43 (1H, s).

The starting material was synthesized in the following manner.

Production Example 366-14-(4-Amino-3-chlorophenoxy)-7-methoxy-6-quinolinecarboxamide

After dissolving 4-amino-3-chlorophenol (1.213 g, 8.45 mmol) indimethylsulfoxide (10 ml), sodium hydride (290 mg, 8.45 mmol) wasgradually added at room temperature and the mixture was stirred for 30minutes. The 7-methoxy-4-chloro-6-quinolinecarboxamide (1.00 g, 4.23mmol) obtained in Production Example 152-3 was added, and the mixturewas heated at 100° C. for 2 hours while stirring. Upon cooling to roomtemperature, the reaction solution was distributed between ethyl acetateand water, and the organic layer was washed with water and saturatedbrine and dried over anhydrous sodium sulfate. The solvent was distilledoff and subjected to silica gel column chromatography (eluent—ethylacetate:methanol=9:1), the fraction containing the target substance wasconcentrated, suspended in tetrahydrofuran and diluted with hexane, andthe crystals were filtered out and blow-dried to obtain the titlecompound (1.216 g, 3.54 mmol, 83.7%) as light brown crystals.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 4.10 (2H, s), 4.13 (3H, s), 5.90 (1H,br), 6.46 (1H, d, J=5.6 Hz), 6.86 (1H, m), 6.93 (1H, dd, J=2.4, 8.4 Hz),7.13 (1H, d, J=2.4 Hz), 7.53 (1H, s), 7.80 (1H, br), 8.64 (1H, d, J=5.6Hz), 9.27 (1H, s).

Example 3674-(3-Chloro-4-((2-thiazolylamino)carbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (38.3 mg, 0.082 mmol, 56.2%) was obtained as lightbrown crystals from4-(4-amino-3-chlorophenoxy)-7-methoxy-6-quinolinecarboxamide (50 mg,0.145 mmol) and phenyl N-(1,3-thiazol-2-yl)carbamate, by the sameprocedure as in Example 131.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 4.02 (3H, s), 6.56 (1H, d, J=5.2 Hz),7.15 (1H, s), 7.31 (1H, d, J=8.0 Hz), 7.40 (1H, s), 7.51 (1H, s), 7.59(1H, s), 7.73 (1H, s), 7.85 (1H, s), 8.27 (1H, d, J=8.0 Hz), 8.65 (1H,s), 8.67 (1H, d, J=5.2 Hz), 11.19 (1H, s).

Example 3684-(3-Chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (22.4 mg, 0.052 mmol, 34.8%) was obtained as whitecrystals from phenylN-(4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2-chlorophenyl)carbamate (70mg, 0.15 mmol) and cyclopropylamine, by the same procedure as in Example11.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.41 (2H, m), 0.66 (2H, m), 2.56 (1H,m), 4.01 (3H, s), 6.51 (1H, d, J=5.6 Hz), 7.18 (1H, d, J=2.8 Hz), 7.23(1H, dd, J=2.8, 8.8 Hz), 7.48 (1H, d, J=2.8 Hz), 7.50 (1H, s), 7.72 (1H,s), 7.84 (1H, s), 7.97 (1H, s), 8.25 (1H, d, J=8.8 Hz), 8.64 (1H, s),8.65 (1H, d, J=5.6 Hz).

The starting material was synthesized in the following manner.

Production Example 368-1 PhenylN-(4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2-chlorophenyl)carbamate

The title compound (708 mg, 1.526 mmol, 87.4%) was obtained as lightbrown crystals from4-(4-amino-3-chlorophenoxy)-7-methoxy-6-quinolinecarboxamide (600 mg,1.745 mmol), by the same procedure as in Production Example 17.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 4.14 (3H, s), 5.89 (1H, br), 6.50 (1H,d, J=5.6 Hz), 7.16 (2H, dd, J=2.4, 8.8 Hz), 7.22-7.30 (4H, m), 7.44 (2H,m), 7.55 (1H, s), 7.81 (1H, br), 8.31 (1H, d, J=8.8 Hz), 8.68 (1H, d,J=5.6 Hz), 9.27 (1H, s).

Example 3694-(3-Chloro-4-(2-fluoroethylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (95.8 mg, 0.221 mmol, 51.3%) was obtained as lightbrown crystals from phenylN-(4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2-chlorophenyl)carbamate (200mg, 0.431 mmol) and 2-fluoroethylamine hydrochloride, by the sameprocedure as in Example 11.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.98 (1H, m), 3.46 (1H, m), 4.02 (3H,s), 4.42 (1H, t, J=4.8 Hz), 4.53 (1H, dd, J=4.8, 5.6 Hz), 6.52 (1H, d,J=5.2 Hz), 7.23 (1H, d, J=2.4, 8.8 Hz), 7.29 (1H, m), 7.48 (1H, d, J=2.4Hz), 7.50 (1H, s), 7.72 (1H, s), 7.84 (1H, s), 8.22-8.25 (2H, m),8.64-8.66 (2H, m).

Example 3707-Benzyloxy-4-(4-(cyclopropylaminocarbonyl)amino-3-fluorophenoxy)-6-quinolinecarboxamide

The title compound (663 mg, 1.363 mmol, 93.9%) was obtained as lightyellow crystals from phenylN-(4-(7-benzyloxy-6-carbamoyl-4-quinolyl)oxy-2-fluorophenyl)carbamate(760 mg, 1.452 mmol) and cyclopropylamine, by the same procedure as inExample 11.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.41 (2H, m), 0.65 (2H, m), 2.56 (1H,m), 5.44 (2H, s), 6.54 (1H, d, J=5.6 Hz), 6.82 (1H, d, J=2.8 Hz), 7.08(1H, m), 7.33 (1H, dd, J=2.8, 12.0 Hz), 7.38 (1H, d, J=7.2 Hz), 7.44(2H, m), 7.58 (2H, d, J=7.2 Hz), 7.61 (1H, s), 7.75 (1H, s), 7.84 (1H,s), 8.20-8.24 (2H, m), 8.63 (1H, s), 8.66 (1H, d, J=5.6 Hz).

The starting material was synthesized in the following manner.

Production Example 370-14-(4-Amino-3-fluorophenoxy)-7-(benzyloxy)-6-quinolinecarboxamide

The title compound (752 mg, 1.86 mmol, 31.6%) was obtained as lightbrown crystals from the4-(4-amino-3-fluorophenoxy)-7-benzyloxy-6-cyanoquinoline (2.27 g, 5.89mmol) described in Production Example 8, by the same procedure as inExample 112.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 3.77 (2H, s), 5.34 (2H, s), 5.78 (1H,br), 6.47 (1H, d, J=5.2 Hz), 6.79-6.91 (3H, m), 7.41-7.54 (5H, m), 7.62(1H, s), 7.81 (1H, br), 8.65 (1H, d, J=5.2 Hz), 9.31 (1H, s).

Production Example 370-2 PhenylN-(4-(7-benzyloxy-6-carbamoyl-4-quinolyl)oxy-2-fluorophenyl)carbamate

The title compound (760 mg, 1.452 mmol, 77.9%) was obtained as lightyellow crystals from4-(4-amino-3-fluorophenoxy)-7-(benzyloxy)-6-quinolinecarboxamide (752mg, 1.864 mmol), by the same procedure as in Production Example 17.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 5.35 (2H, s), 5.80 (1H, br), 6.52 (1H,d, J=5.2 Hz), 7.03 (2H, m), 7.22-7.30 (4H, m), 7.41-7.49 (5H, m), 7.53(2H, d, J=6.8 Hz), 7.64 (1H, s), 7.82 (1H, br), 8.24 (1H, br), 8.69 (1H,d, J=5.2 Hz), 9.30 (1H, s).

Example 371 4-(4-(Cyclopropylaminocarbonyl)amino-3-fluorophenoxy)-7-hydroxy-6-quinolinecarboxamide

The title compound (498 mg, 1.256 mmol, 95.5%) was obtained as lightyellow crystals from 7-benzyloxy-4-(4-(cyclopropylaminocarbonyl)amino-3-fluorophenoxy)-6-quinolinecarboxamide (640 mg, 1.316 mmol), bythe same procedure as in Example 83.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.41 (2H, m), 0.66 (2H, m), 2.57 (1H,m), 6.42 (1H, d, J=5.2 Hz), 6.83 (1H, s), 7.31 (1H, d, J=9.2 Hz), 7.30(1H, s), 7.34 (1H, dd, J=2.8, 11.6 Hz), 8.08 (1H, s), 8.21-8.26 (2H, m),8.61 (1H, d, J=5.2 Hz), 8.91 (1H, br), 8.96 (1H, s).

Example 3724-(4-(Cyclopropylaminocarbonyl)amino-3-fluorophenoxy)-7-(3-(N,N-diethylamino)propoxy)-6-quinolinecarboxamide

The title compound (34.2 mg, 0.067 mmol, 53.2%) was obtained as lightyellow crystals from4-(4-(cyclopropylaminocarbonyl)amino-3-fluorophenoxy)-7-hydroxy-6-quinolinecarboxamide(50 mg, 0.126 mmol) and N-(3-chloropropyl)-N,N-diethylaminehydrochloride, by the same procedure as in Example 7.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.41 (2H, m), 0.65 (2H, m), 0.95 (6H,t, J=7.2 Hz), 1.96 (2H, m), 2.44-2.49 (4H, m), 2.57-2.59 (3H, m), 4.30(2H, m), 6.52 (1H, d, J=5.2 Hz), 6.70 (1H, s), 7.09 (1H, d, J=10.8 Hz),7.32 (1H, m), 7.50 (1H, s), 7.79 (1H, s), 7.91 (1H, s), 8.19-8.22 (2H,m), 8.66 (1H, d, J=5.2 Hz), 8.69 (1H, s).

Example 3734-(4-(Cyclopropylaminocarbonyl)amino-3-fluorophenoxy)-7-(2-(N,N-diethylamino)ethoxy)-6-quinolinecarboxamide

The title compound (20.6 mg, 0.042 mmol, 33.0%) was obtained as lightyellow crystals from4-(4-(cyclopropylaminocarbonyl)amino-3-fluorophenoxy)-7-hydroxy-6-quinolinecarboxamide(50 mg, 0.126 mmol) and N-(2-bromoethyl)-N,N-diethylamine hydrobromide,by the same procedure as in Example 7.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.41 (2H, m), 0.65 (2H, m), 0.97 (6H,t, J=7.2 Hz), 2.50-2.58 (5H, m), 2.85 (2H, m), 4.36 (2H, m), 6.52 (1H,d, J=5.2 Hz), 6.81 (1H, s), 7.09 (1H, d, J=6.8 Hz), 7.34 (1H, d, J=11.6Hz), 7.57 (1H, s), 7.81 (1H, s), 8.19-8.22 (2H, m), 8.31 (1H, s), 8.67(1H, d, J=5.2 Hz), 8.80 (1H, s).

Example 3744-(4-(Cyclopropylaminocarbonyl)amino-3-fluorophenoxy)-7-(3-(4-morpholino)propoxy)-6-quinolinecarboxamide

The title compound (35.0 mg, 0.067 mmol, 53.0%) was obtained as yellowcrystals from4-(4-(cyclopropylaminocarbonyl)amino-3-fluorophenoxy)-7-hydroxy-6-quinolinecarboxamide(50 mg, 0.126 mmol) and N-(3-chloropropyl)morpholine, by the sameprocedure as in Example 7.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.41 (2H, m), 0.65 (2H, m), 2.01 (2H,m), 2.39 (4H, br), 2.46-2.50 (2H, m), 2.56 (1H, m), 3.59 (4H, m), 4.31(2H, m), 6.52 (1H, d, J=5.2 Hz), 6.82 (1H, s), 7.08 (1H, d, J=8.4 Hz),7.31 (1H, m), 7.52 (1H, s), 7.78 (2H, s), 8.19-8.24 (2H, m), 8.65-8.67(2H, m).

Example 3754-(4-(Cyclopropylaminocarbonyl)amino-3-fluorophenoxy)-7-(2-(4-morpholino)ethoxy)-6-quinolinecarboxamide

The title compound (35.1 mg, 0.069 mmol, 54.6%) was obtained as yellowcrystals from4-(4-(cyclopropylaminocarbonyl)amino-3-fluorophenoxy)-7-hydroxy-6-quinolinecarboxamide(50 mg, 0.126 mmol) and N-(2-chloroethyl)morpholine hydrochloride, bythe same procedure as in Example 7.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.41 (2H, m), 0.65 (2H, m), 2.50-2.56(5H, m), 2.79 (2H, m), 3.60 (4H, br), 4.41 (2H, m), 6.53 (1H, d, J=5.2Hz), 6.81 (1H, s), 7.08 (1H, d, J=9.6 Hz), 7.33 (1H, d, J=12.8 Hz), 7.58(1H, s), 7.87 (1H, s), 8.19-8.23 (2H, m), 8.39 (1H, s), 8.67 (1H, d,J=5.2 Hz), 8.82 (1H, s).

Example 3764-(4-(Cyclopropylaminocarbonyl)amino-3-fluorophenoxy)-7-((2-pyridyl)methoxy)-6-quinolinecarboxamide

The title compound (20.2 mg, 0.041 mmol, 32.8%) was obtained as lightbrown crystals from4-(4-(cyclopropylaminocarbonyl)amino-3-fluorophenoxy)-7-hydroxy-6-quinolinecarboxamide(50 mg, 0.126 mmol) and 2-chloromethylpyridine hydrochloride, by thesame procedure as in Example 7.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.41 (2H, m), 0.65 (2H, m), 2.56 (1H,m), 5.53 (2H, s), 6.54 (1H, d, J=5.2 Hz), 6.80 (1H, s), 7.08 (1H, d,J=10.4 Hz), 7.30-7.40 (2H, m), 7.59 (1H, s), 7.62 (1H, d, J=8.0 Hz),7.79 (1H, s), 7.86 (1H, dd, J=2.0, 7.6 Hz), 8.19-8.23 (3H, m), 8.61-8.68(3H, m).

Example 3774-(4-(Cyclopropylaminocarbonyl)amino-3-fluorophenoxy)-7-((3-pyridyl)methoxy)-6-quinolinecarboxamide

The title compound (20.2 mg, 0.041 mmol, 32.8%) was obtained as lightyellow crystals from4-(4-(cyclopropylaminocarbonyl)amino-3-fluorophenoxy)-7-hydroxy-6-quinolinecarboxamide(50 mg, 0.126 mmol) and 3-chloromethylpyridine hydrochloride, by thesame procedure as in Example 7.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.41 (2H, m), 0.65 (2H, m), 2.56 (1H,m), 5.47 (2H, s), 6.55 (1H, d, J=5.2 Hz), 6.81 (1H, s), 7.08 (1H, d,J=10.0 Hz), 7.32 (1H, d, J=12.4 Hz), 7.45 (1H, m), 7.64 (1H, s), 7.73(1H, s), 7.83 (1H, s), 7.98 (1H, m), 8.23 (2H, br), 8.57 (2H, br), 8.66(1H, d, J=5.2 Hz), 8.80 (1H, s).

Example 3784-(4-(Cyclopropylaminocarbonyl)amino-3-fluorophenoxy)-7-((4-pyridyl)methoxy)-6-quinolinecarboxamide

The title compound (29.8 mg, 0.061 mmol, 48.5%) was obtained as lightyellow crystals from4-(4-(cyclopropylaminocarbonyl)amino-3-fluorophenoxy)-7-hydroxy-6-quinolinecarboxamide(50 mg, 0.126 mmol) and 4-chloromethylpyridine hydrochloride, by thesame procedure as in Example 7.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.41 (2H, m), 0.65 (2H, m), 2.56 (1H,m), 5.50 (2H, s), 6.54 (1H, d, J=5.2 Hz), 6.80 (1H, s), 7.07 (1H, d,J=8.0 Hz), 7.32 (1H, d, J=11.6 Hz), 7.53-7.55 (3H, m), 7.76 (1H, s),7.92 (1H, s), 8.19-8.22 (2H, m), 8.55 (1H, s), 8.60-8.66 (3H, m).

Example 3797-Benzyloxy-4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-6-quinolinecarboxamide

The title compound (2.433 g, 4.84 mmol, 87.9%) was obtained as lightyellow crystals from phenylN-(4-(7-benzyloxy-6-carbamoyl-4-quinolyl)oxy-2-chlorophenyl)carbamate(2.97 g, 5.50 mmol) and cyclopropylamine, by the same procedure as inExample 11.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.41 (2H, m), 0.65 (2H, m), 2.56 (1H,m), 5.41 (2H, s), 6.51 (1H, d, J=5.6 Hz), 7.18 (1H, d, J=2.8 Hz), 7.22(1H, m), 7.35 (1H, d, J=7.2 Hz), 7.42 (2H, m), 7.48 (1H, s), 7.55 (2H,d, J=7.2 Hz), 7.59 (1H, s), 7.73 (1H, s), 7.82 (1H, s), 7.97 (1H, s),8.25 (1H, d, J=9.2 Hz), 8.60 (1H, s), 8.64 (1H, d, J=5.6 Hz).

The starting material was synthesized in the following manner.

Production Example 379-14-(4-Amino-3-chlorophenoxy)-7-benzyloxy-6-cyanoquinoline

After dissolving 4-amino-3-chlorophenol (10.77 g, 75.0 mmol) indimethylsulfoxide (150 ml), sodium hydride (3.00 g, 75.0 mmol) wasgradually added at room temperature and the mixture was stirred for 30minutes. 7-Benzyloxy-4-chloro-6-cyanoquinoline (14.737 g, 50.0 mmol)obtained by a publicly known method was added, and the mixture washeated at 100° C. for 2 hours while stirring. Upon cooling to roomtemperature, the reaction solution was distributed between ethyl acetateand water, and the organic layer was washed with water and saturatedbrine and dried over anhydrous sodium sulfate. The solvent was distilledoff and subjected to silica gel column chromatography (eluent—ethylacetate), the fraction containing the target substance was concentrated,suspended in ethyl acetate and diluted with hexane, and the crystalswere filtered out and blow-dried to obtain the title compound (11.777 g,29.3 mmol, 58.6%) as light brown crystals.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 4.13 (2H, s), 5.35 (2H, s), 6.47 (1H,d, J=5.2 Hz), 6.85 (1H, d, J=8.8 Hz), 6.92 (1H, dd, J=2.4, 9.2 Hz), 7.13(1H, d, J=2.4 Hz), 7.36 (1H, d, J=7.6 Hz), 7.42 (2H, m), 7.51-7.55 (3H,m), 8.65 (1H, d, J=5.2 Hz), 8.69 (1H, s).

Production Example 379-24-(4-Amino-3-chlorophenoxy)-7-(benzyloxy)-6-quinolinecarboxamide

The title compound (5.74 g, 13.7 mmol, 37.8%) was obtained as lightbrown crystals from4-(4-amino-3-chlorophenoxy)-7-benzyloxy-6-cyanoquinoline (14.55 g, 36.2mmol), by the same procedure as in Example 112.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 4.10 (2H, s), 5.34 (2H, s), 5.78 (1H,br), 6.47 (1H, d, J=5.2 Hz), 6.85 (1H, d, J=8.4 Hz), 6.92 (1H, dd,J=2.4, 8.4 Hz), 7.13 (1H, d, J=2.4 Hz), 7.38-7.53 (4H, m), 7.62 (1H, s),7.82 (1H, br), 8.62 (1H, s), 8.64 (1H, d, J=5.2 Hz), 9.30 (1H, s).

Production Example 379-3 PhenylN-(4-(7-benzyloxy-6-carbamoyl-4-quinolyl)oxy-2-chlorophenyl)carbamate

The title compound (2.97 g, 5.50 mmol, 55.0%) was obtained as lightbrown crystals from4-(4-amino-3-chlorophenoxy)-7-(benzyloxy)-6-quinolinecarboxamide (4.20g, 10.0 mmol), by the same procedure as in Production Example 17.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 5.35 (2H, s), 5.81 (1H, br), 6.51 (1H,d, J=5.2 Hz), 7.16 (1H, dd, J=2.8, 8.8 Hz), 7.22-7.30 (4H, m), 7.41-7.54(8H, m), 7.64 (1H, s), 7.81 (1H, br), 8.32 (1H, d, J=9.2 Hz), 8.69 (1H,d, J=5.2 Hz), 9.30 (1H, s).

Example 3804-(3-Chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-hydroxy-6-quinolinecarboxamide

The title compound (697 mg, 1.69 mmol, 83.6%) was obtained as yellowcrystals from7-benzyloxy-4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-6-quinolinecarboxamide(1.016 g, 2.02 mmol) by the same procedure as in Example 83.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.43 (2H, m), 0.68 (2H, m), 2.58 (1H,m), 6.56 (1H, d, J=5.6 Hz), 7.23 (1H, s), 7.30 (1H, m), 7.36 (1H, s),7.55 (1H, d, J=2.4 Hz), 8.01 (1H, s), 8.19 (1H, s), 8.33 (1H, d, J=9.2Hz), 8.72 (1H, d, J=5.6 Hz), 8.82 (1H, s), 9.01 (1H, s).

Example 3814-(3-Chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxamide

The title compound (29.9 mg, 0.063 mmol, 52.4%) was obtained as lightyellow crystals from4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-hydroxy-6-quinolinecarboxamide(50 mg, 0.121 mmol) and 2-methoxyethylbromide, by the same procedure asin Example 7.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.41 (2H, m), 0.65 (2H, m), 2.57 (1H,m), 3.36 (3H, s), 3.81 (2H, m), 4.41 (2H, m), 6.53 (1H, d, J=5.2 Hz),7.20 (1H, d, J=2.8 Hz), 7.25 (1H, dd, J=2.8, 9.2 Hz), 7.41 (1H, d, J=2.8Hz), 7.57 (1H, s), 7.82 (1H, s), 7.83 (1H, s), 7.99 (1H, s), 8.28 (1H,d, J=9.2 Hz), 8.68 (1H, d, J=5.2 Hz), 8.77 (1H, s).

Example 3824-(3-Chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-(3-(4-morpholino)propoxy)-6-quinolinecarboxamide

The title compound (30.5 mg, 0.056 mmol, 46.6%) was obtained as lightyellow crystals from4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-hydroxy-6-quinolinecarboxamide(50 mg, 0.121 mmol) and N-(3-chloropropyl)morpholine, by the sameprocedure as in Example 7.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.41 (2H, m), 0.65 (2H, m), 2.02 (2H,m), 2.39 (4H, br), 2.46-2.59 (3H, m), 3.59 (4H, m), 4.31 (2H, m), 6.53(1H, d, J=5.2 Hz), 7.20 (1H, d, J=2.8 Hz), 7.25 (1H, dd, J=2.8, 9.2 Hz),7.49 (1H, d, J=2.8 Hz), 7.52 (1H, s), 7.78 (2H, s), 7.98 (1H, s), 8.28(1H, d, J=9.2 Hz), 8.65 (1H, s), 8.66 (1H, d, J=5.2 Hz).

Example 3834-(3-Chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-(2-(4-morpholino)ethoxy)-6-quinolinecarboxamide

The title compound (29.8 mg, 0.057 mmol, 46.8%) was obtained as lightyellow crystals from4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-hydroxy-6-quinolinecarboxamide(50 mg, 0.121 mmol) and N-(2-chloroethyl)morpholine hydrochloride, bythe same procedure as in Example 7.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.41 (2H, m), 0.65 (2H, m), 2.50-2.56(5H, m), 2.80 (2H, m), 3.60 (4H, br), 4.41 (2H, m), 6.53 (1H, d, J=5.2Hz), 7.20 (1H, d, J=2.8 Hz), 7.25 (1H, dd, J=2.8, 8.8 Hz), 7.50 (1H, d,J=2.8 Hz), 7.58 (1H, s), 7.87 (1H, s), 7.99 (1H, s), 8.27 (1H, d, J=8.8Hz), 8.38 (1H, s), 8.67 (1H, d, J=5.2 Hz), 8.82 (1H, s).

Example 3844-(3-Chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-(3-(1-piperidino)propoxy)-6-quinolinecarboxamide

The title compound (27.3 mg, 0.051 mmol, 41.9%) was obtained as lightyellow crystals from4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-hydroxy-6-quinolinecarboxamide(50 mg, 0.121 mmol) and 1-(3-chloropropyl)piperidine hydrochloride, bythe same procedure as in Example 7.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.42 (2H, m), 0.65 (2H, m), 1.36 (2H,m), 1.47 (4H, m), 1.99 (2H, m), 2.33 (4H, br), 2.42 (2H, m), 2.56 (1H,m), 4.27 (2H, m), 6.50 (1H, d, J=5.2 Hz), 7.18 (1H, d, J=2.8 Hz), 7.22(1H, dd, J=2.8, 8.8 Hz), 7.47 (1H, d, J=2.8 Hz), 7.49 (1H, s), 7.76 (2H,br), 7.96 (1H, s), 8.25 (1H, d, J=8.8 Hz), 8.64 (1H, d, J=5.2 Hz), 8.65(1H, s).

Example 3854-(3-Chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-(2-(1-pyrrolidino)ethoxy)-6-quinolinecarboxamide

The title compound (24.6 mg, 0.048 mmol, 39.8%) was obtained as lightyellow crystals from4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-hydroxy-6-quinolinecarboxamide(50 mg, 0.121 mmol) and 1-(2-chloroethyl)pyrrolidine hydrochloride, bythe same procedure as in Example 7.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.41 (2H, m), 0.65 (2H, m), 1.67 (4H,br), 2.49-2.58 (5H, m), 2.89 (2H, m), 4.38 (2H, m), 6.51 (1H, d, J=5.2Hz), 7.18 (1H, d, J=2.8 Hz), 7.23 (1H, dd, J=2.8, 9.2 Hz), 7.48 (1H, d,J=2.8 Hz), 7.56 (1H, s), 7.72 (1H, s), 7.96 (1H, s), 8.25 (1H, d, J=9.2Hz), 8.33 (1H, s), 8.65 (1H, d, J=5.2 Hz), 8.76 (1H, s).

Example 3864-(3-Chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-(2-hydroxyethoxy)-6-quinolinecarboxamide

The title compound (63.7 mg, 0.139 mmol, 27.9%) was obtained as lightyellow crystals from4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-hydroxy-6-quinolinecarboxamide(206 mg, 0.499 mmol) and 2-bromoethanol, by the same procedure as inExample 7.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.41 (2H, m), 0.65 (2H, m), 2.56 (1H,m), 3.84 (2H, m), 4.30 (2H, m), 5.12 (1H, t, J=5.2 Hz), 6.51 (1H, d,J=5.2 Hz), 7.19 (1H, d, J=2.8 Hz), 7.24 (1H, dd, J=2.8, 8.8 Hz), 7.49(1H, d, J=2.8 Hz), 7.54 (1H, s), 7.82 (1H, s), 7.94 (1H, s), 7.97 (1H,s), 8.26 (1H, d, J=8.8 Hz), 8.66 (1H, d, J=5.2 Hz), 8.80 (1H, s).

Example 3874-(3-Chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-(3-hydroxypropoxy)-6-quinolinecarboxamide

The title compound (67.0 mg, 0.142 mmol, 28.5%) was obtained as lightyellow crystals from4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-hydroxy-6-quinolinecarboxamide(206 mg, 0.499 mmol) and 3-bromopropanol, by the same procedure as inExample 7.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.41 (2H, m), 0.65 (2H, m), 1.98 (2H,m), 2.56 (1H, m), 3.62 (2H, m), 4.32 (2H, m), 4.69 (1H, m), 6.50 (1H, d,J=5.2 Hz), 7.18-7.24 (2H, m), 7.48-7.50 (2H, m), 7.73 (1H, s), 7.86 (1H,s), 7.97 (1H, s), 8.26 (1H, d, J=8.4 Hz), 8.64 (1H, d, J=5.2 Hz), 8.67(1H, s).

Example 3884-(3-Chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-((4R)-2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-6-quinolinecarboxamide

The title compound (234.4 mg, 0.445 mmol, 44.5%) was obtained as lightyellow crystals from4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-hydroxy-6-quinolinecarboxamide(413 mg, 1.00 mmol) and ((4R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl4-toluenesulfonate, by the same procedure as in Example 7.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.41 (2H, m), 0.65 (2H, m), 1.33 (3H,s), 1.40 (3H, s), 2.56 (1H, m), 3.99 (1H, m), 4.14 (1H, m), 4.27 (1H,m), 4.41 (1H, m), 4.58 (1H, m), 6.51 (1H, d, J=5.2 Hz), 7.20 (1H, d,J=2.8 Hz), 7.25 (1H, dd, J=2.8, 8.8 Hz), 7.49 (1H, d, J=2.8 Hz), 7.57(1H, s), 7.84 (2H, br), 7.99 (1H, s), 8.28 (1H, d, J=8.8 Hz), 8.67 (1H,d, J=5.2 Hz), 8.80 (1H, s).

Example 3894-(3-Chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-((4S)-2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-6-quinolinecarboxamide

The title compound (253 mg, 0.480 mmol, 48.0%) was obtained as lightyellow crystals from4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-hydroxy-6-quinolinecarboxamide(413 mg, 1.00 mmol) and ((4S)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl4-toluenesulfonate), by the same procedure as in Example 7.

Example 3904-(3-Chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-((2R)-2,3-dihydroxypropyl)oxy-6-quinolinecarboxamide

After dissolving4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-((4R)-2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-6-quinolinecarboxamide(219 mg, 0.416 mmol) in trifluoroacetic acid (2 ml)-tetrahydrofuran (2ml)-water (1 ml) at room temperature, the solution was stirred for 1hour. The reaction solution was diluted with water (30 ml), and thensodium bicarbonate (3 g) was gradually added thereto for neutralization,after which extraction was performed with ethyl acetate, and the organiclayer was washed with saturated brine and dried over anhydrous sodiumsulfate. The solvent was distilled off under reduced pressure andsuspended in tetrahydrofuran, and the precipitated crystals werefiltered out, washed with a small amount of ethyl acetate and blow-driedto obtain the title compound (121.4 mg, 0.249 mmol, 60.0%) as whitecrystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.41 (2H, m), 0.65 (2H, m), 2.56 (1H,m), 3.53 (2H, m), 3.94 (1H, m), 4.24 (1H, m), 4.33 (1H, m), 4.83 (1H, t,J=5.6 Hz), 5.26 (1H, d, J=5.6 Hz), 6.53 (1H, d, J=5.2 Hz), 7.20 (1H, d,J=2.8 Hz), 7.26 (1H, dd, J=2.8, 9.2 Hz), 7.51 (1H, d, J=2.8 Hz), 7.54(1H, s), 7.84 (1H, s), 7.99 (2H, br), 8.28 (1H, d, J=9.2 Hz), 8.67 (1H,d, J=5.2 Hz), 8.81 (1H, s).

Example 391-14-(3-Chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-((2S)-2,3-dihydroxypropyl)oxy-6-quinolinecarboxamide

After dissolving4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-((4S)-2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-6-quinolinecarboxamide(236 mg, 0.448 mmol) in trifluoroacetic acid (2 ml)-tetrahydrofuran (2ml)-water (1 ml) at room temperature, the solution was stirred for 1hour. The reaction solution was diluted with water (30 ml), and thensodium bicarbonate (3 g) was gradually added thereto for neutralization,after which extraction was performed with ethyl acetate, and the organiclayer was washed with saturated brine and dried over anhydrous sodiumsulfate. The solvent was distilled off under reduced pressure andsuspended in tetrahydrofuran, and the precipitated crystals werefiltered out, washed with a small amount of ethyl acetate and blow-driedto obtain the title compound (115.6 mg, 0.237 mmol, 53.0%) as whitecrystals.

Example 391-24-(3-Chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-(1,3-dioxolan-2-yl)methoxy)-6-quinolinecarboxamide

The title compound (71.2 mg, 0.143 mmol, 19.0%) was obtained as whitecrystals from4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-hydroxy-6-quinolinecarboxamide(310 mg, 0.75 mmol) and 2-(bromomethyl)-1,3-dioxolane, by the sameprocedure as in Example 7.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.42 (2H, m), 0.65 (2H, m), 2.56 (1H,m), 3.92-4.02 (4H, m), 4.36 (2H, m), 5.36 (1H, m), 6.53 (1H, d, J=5.2Hz), 7.20 (1H, d, J=2.8 Hz), 7.26 (1H, dd, J=2.8, 8.8 Hz), 7.51 (1H, d,J=2.8 Hz), 7.58 (1H, s), 7.81 (1H, s), 7.83 (1H, s), 7.99 (1H, s), 8.28(1H, d, J=8.8 Hz), 8.68 (1H, d, J=5.2 Hz), 8.75 (1H, s).

Example 3924-(3-Chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-(3-(N,N-diethylamino)propyl)oxy)-6-quinolinecarboxamide

The title compound (119.6 mg, 0.227 mmol, 37.5%) was obtained as lightyellow crystals from4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-hydroxy-6-quinolinecarboxamide(250 mg, 0.606 mmol) and N-(3-chloropropyl)-N,N-diethylaminehydrochloride, by the same procedure as in Example 7.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.42 (2H, m), 0.65 (2H, m), 0.95 (6H,t, J=7.2 Hz), 1.96 (2H, m), 2.45-2.59 (7H, m), 4.30 (2H, m), 6.52 (1H,d, J=5.2 Hz), 7.20 (1H, d, J=2.8 Hz), 7.24 (1H, dd, J=2.8, 9.2 Hz), 7.49(1H, d, J=2.8 Hz), 7.50 (1H, s), 7.79 (1H, s), 7.86 (1H, s), 7.99 (1H,s), 8.27 (1H, d, J=9.2 Hz), 8.66 (1H, d, J=5.2 Hz), 8.69 (1H, s).

Example 393 tert-Butyl4-(((6-(aminocarbonyl)-4-(3-chloro-4-((cyclopropylamino)carbonyl)amino)phenoxy)-7-quinolyl)oxy)methyl)-1-piperidinecarboxylate

The title compound (460 mg, 0.754 mmol, 44.5%) was obtained as whitecrystals from4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-hydroxy-6-quinolinecarboxamide(700 mg, 1.696 mmol) and tert-butyl4-(bromomethyl)-1-piperidinecarboxylate, by the same procedure as inExample 7.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.42 (2H, m), 0.65 (2H, m), 1.17-1.25(3H, m), 1.39 (9H, s), 1.79 (2H, m), 2.10 (1H, m), 2.56 (1H, m), 2.74(1H, m), 4.01 (2H, m), 4.12 (2H, m), 6.51 (1H, d, J=5.2 Hz), 7.18 (1H,d, J=2.8 Hz), 7.22 (1H, dd, J=2.8, 9.2 Hz), 7.47 (1H, d, J=2.8 Hz), 7.50(1H, s), 7.70 (1H, br), 7.71 (1H, br), 7.97 (1H, s), 8.25 (1H, d, J=9.2Hz), 8.55 (1H, s), 8.64 (1H, d, J=5.2 Hz).

Example 3944-(3-Chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-((1-methyl-4-piperidyl)methoxy)-6-quinolinecarboxamide

After dissolving tert-butyl4-(((6-(aminocarbonyl)-4-(3-chloro-4-((cyclopropylamino)carbonyl)amino)phenoxy)-7-quinolyl)oxy)methyl)-1-piperidinecarboxylate(460 mg, 0.754 mmol) in trifluoroacetic acid (2.3 ml) at roomtemperature, the solution was stirred for 2 hours. The reaction solutionwas concentrated under reduced pressure, saturated aqueous sodiumbicarbonate was gradually added for neutralization, and the mixture wasextracted with ethyl acetate and dried over anhydrous sodium sulfate.The solvent was distilled off under reduced pressure to obtain4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-((4-piperidyl)methoxy)-6-quinolinecarboxamide as a crudeproduct. This was dissolved in tetrahydrofuran (10 ml)-water (10 ml),and then a 37% aqueous formaldehyde solution (1 ml), acetic acid (0.086ml, 1.51 mmol) and sodium cyanoborohydride (95 mg, 1.51 mmol) were addedat room temperature and the mixture was stirred for 20 minutes. Thereaction solution was distributed between ethyl acetate and water, andthe organic layer was washed with saturated brine and dried overanhydrous sodium sulfate. After distilling off the solvent, the residuewas subjected to silica gel column chromatography (eluent—ethylacetate), the fraction containing the target substance was concentratedand suspended in ethyl acetate, and the suspension was diluted withhexane and the crystals filtered out and blow-dried to obtain the titlecompound (226.1 mg, 0.431 mmol, two stages, 57.2%) as white crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.41 (2H, m), 0.65 (2H, m), 1.37 (2H,m), 1.74-1.89 (5H, m), 2.15 (3H, s), 2.56 (1H, m), 2.79 (2H, m), 4.11(2H, m), 6.51 (1H, d, J=5.2 Hz), 7.18 (1H, d, J=2.8 Hz), 7.22 (1H, dd,J=2.8, 9.2 Hz), 7.47 (1H, d, J=2.8 Hz), 7.49 (1H, s), 7.70 (1H, s), 7.74(1H, s), 7.96 (1H, s), 8.25 (1H, d, J=9.2 Hz), 8.59 (1H, s), 8.64 (1H,d, J=5.2 Hz).

Example 395 Methyl4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylate

The title compound (2.894 g, 6.55 mmol, 98.5%) was obtained as lightbrown crystals from phenylN-(2-chloro-4-(7-methoxy-6-methoxycarbonyl-4-quinolyl)oxyphenyl)carbamate(3.184 g, 6.65 mmol) and cyclopropylamine, by the same procedure as inExample 11.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.41 (2H, m), 0.65 (2H, m), 2.56 (1H,m), 3.85 (3H, s), 3.96 (3H, s), 6.52 (1H, d, J=5.2 Hz), 7.19 (1H, d,J=2.8 Hz), 7.24 (1H, dd, J=2.8, 9.2 Hz), 7.50 (1H, d, J=2.8 Hz), 7.52(1H, s), 7.97 (1H, s), 8.26 (1H, d, J=9.2 Hz), 8.56 (1H, s), 8.68 (1H,d, J=5.2 Hz).

The starting material was synthesized in the following manner.

Production Example 395-1 Methyl4-(4-amino-3-chlorophenoxy)-7-methoxy-6-quinolinecarboxylate

After dissolving 4-amino-3-chlorophenol (3.17 g, 22.05 mmol) indimethylsulfoxide (50 ml), sodium hydride (882 mg, 22.05 mmol) wasgradually added at room temperature and the mixture was stirred for 30minutes. The 4-chloro-7-methoxy-6-methoxycarbonylquinoline (3.70 g, 14.7mmol) described in WO0050405 was added, and the mixture was heated at100° C. for 3 hours. After standing to cool to room temperature, thereaction solution was distributed between ethyl acetate and water, andthe organic layer was washed with water and saturated brine and driedover anhydrous sodium sulfate. The solvent was distilled off, silica gelcolumn chromatography (eluent—ethyl acetate) was performed, the fractioncontaining the target substance was concentrated, suspended in ethylacetate and diluted with hexane, and the crystals were filtered out andblow-dried to obtain the title compound (3.092 g, 8.62 mmol, 57.4%) aslight brown crystals.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 3.98 (3H, s), 4.06 (3H, s), 4.12 (2H,s), 6.44 (1H, d, J=5.2 Hz), 6.86 (1H, d, J=8.8 Hz), 6.95 (1H, dd, J=2.8,8.8 Hz), 7.16 (1H, d, J=2.8 Hz), 7.49 (1H, s), 8.64 (1H, d, J=5.2 Hz),8.80 (1H, s).

Production Example 395-2 PhenylN-(2-chloro-4-(7-methoxy-6-methoxycarbonyl-4-quinolyl)oxyphenyl)carbamate

The title compound (3.184 g, 6.65 mmol, 77.2%) was obtained as lightbrown crystals from methyl4-(4-amino-3-chlorophenoxy)-7-methoxy-6-quinolinecarboxylate (3.09 g,8.61 mmol) in the same manner as Production Example 17.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 3.98 (3H, s), 4.06 (3H, s), 6.48 (1H,d, J=5.2 Hz), 7.17 (1H, dd, J=2.8, 9.2 Hz), 7.21-7.31 (4H, m), 7.41-7.46(2H, m), 7.50 (2H, br), 8.32 (1H, d, J=8.8 Hz), 8.67 (1H, d, J=5.2 Hz),8.77 (1H, s).

Example 3964-(3-Chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid

After adding methanol (48 ml) and 2N aqueous sodium hydroxide (16 ml) tomethyl4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylate(2.87 g, 6.50 mmol), the mixture was stirred at room temperature for 1.5hours and at 60° C. for 15 minutes. The reaction solution was allowed tocool to room temperature, and after neutralization by addition of 1Nhydrochloric acid, the methanol was distilled off and the precipitatedlight brown crystals were filtered out, thoroughly washed with water anddried at 70° C. to obtain the title compound (2.628 g, 6.14 mmol,94.6%).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.42 (2H, m), 0.65 (2H, m), 2.56 (1H,m), 3.96 (3H, s), 6.51 (1H, d, J=5.2 Hz), 7.17-7.26 (2H, m), 7.49 (2H,s), 7.96 (1H, s), 8.26 (1H, d, J=9.2 Hz), 8.52 (1H, s), 8.66 (1H, d,J=5.2 Hz), 13.08 (1H, br).

Example 397N6-Cyclopropyl-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

After dissolving4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid (86 mg, 0.20 mmol) in dimethylformamide (2 ml), there were added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (77 mg, 0.40mmol), 1-hydroxy-1H-benzotriazole monohydrate (61 mg, 0.40 mmol),triethylamine (0.112 ml, 0.80 mmol) and cyclopropylamine (0.055 ml)while stirring on ice, and the mixture was stirred overnight at roomtemperature. The reaction solution was distributed between ethyl acetateand water, and the organic layer was washed with water and saturatedbrine and then dried over anhydrous sodium sulfate. After distilling offthe solvent, the residue was suspended in ethyl acetate and diluted withhexane, and the crystals were filtered out and blow-dried to obtain thetitle compound (40.0 mg, 0.086 mmol, 42.6%) as white crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.41 (2H, m), 0.57 (2H, m), 0.65 (2H,m), 0.69 (2H, m), 2.57 (1H, m), 2.86 (1H, m), 3.97 (3H, s), 6.51 (1H, d,J=5.2 Hz), 7.18 (1H, d, J=2.8 Hz), 7.21 (1H, dd, J=2.8, 9.2 Hz), 7.46(1H, d, J=2.8 Hz), 7.47 (1H, s), 7.97 (1H, s), 8.26 (1H, d, J=9.2 Hz),8.33 (1H, m), 8.40 (1H, s), 8.64 (1H, d, J=5.2 Hz).

Example 398N6-(2-Methoxyethyl)-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (17.8 mg, 0.037 mmol, 18.3%) was obtained as whitecrystals from4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid (86 mg, 0.20 mmol) and 2-methoxyethylamine, by the same procedureas in Example 397.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.42 (2H, m), 0.65 (2H, m), 2.57 (1H,m), 3.29 (3H, s), 3.47 (4H, s), 4.01 (3H, s), 6.51 (1H, d, J=5.2 Hz),7.18 (1H, d, J=2.8 Hz), 7.22 (1H, dd, J=2.8, 9.2 Hz), 7.48 (1H, d, J=2.8Hz), 7.51 (1H, s), 7.97 (1H, s), 8.26 (1H, d, J=9.2 Hz), 8.43 (1H, s),8.59 (1H, s), 8.65 (1H, d, J=5.2 Hz).

Example 399N6-(2-(4-Morpholino)ethyl)-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (62.9 mg, 0.116 mmol, 57.9%) was obtained as lightbrown crystals from4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid (86 mg, 0.20 mmol) and N-(2-aminoethyl)morpholine, by the sameprocedure as in Example 397.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.42 (2H, m), 0.65 (2H, m), 2.43 (4H,br), 2.47-2.51 (2H, m), 2.56 (1H, m), 3.43 (2H, m), 3.60 (4H, m), 4.04(3H, s), 6.51 (1H, d, J=5.2 Hz), 7.18 (1H, d, J=2.8 Hz), 7.22 (1H, dd,J=2.8, 9.2 Hz), 7.48 (1H, d, J=2.8 Hz), 7.52 (1H, s), 7.97 (1H, s), 8.26(1H, d, J=9.2 Hz), 8.48 (1H, m), 8.66 (1H, d, J=5.2 Hz), 8.67 (1H, s).

Example 400N6-(3-(4-Morpholino)propyl)-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (84.7 mg, 0.153 mmol, 76.1%) was obtained as lightbrown crystals from4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid (86 mg, 0.20 mmol) and N-(3-aminopropyl)morpholine, by the sameprocedure as in Example 397.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.42 (2H, m), 0.65 (2H, m), 1.69 (2H,m), 2.33-2.37 (6H, m), 2.56 (1H, m), 3.30-3.37 (2H, m), 3.56 (4H, m),4.02 (3H, s), 6.51 (1H, d, J=5.6 Hz), 7.20 (1H, d, J=2.8 Hz), 7.23 (1H,dd, J=2.8, 9.2 Hz), 7.48 (1H, d, J=2.8 Hz), 7.52 (1H, s), 7.98 (1H, s),8.27 (1H, d, J=9.2 Hz), 8.40 (1H, m), 8.52 (1H, s), 8.66 (1H, d, J=5.6Hz).

Example 401N6-(2-(Diethylamino)ethyl)-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (67.7 mg, 0.129 mmol, 64.0%) was obtained as lightbrown crystals from4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid (86 mg, 0.20 mmol) and N-(2-aminoethyl)-N,N-diethylamine, by thesame procedure as in Example 397.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.42 (2H, m), 0.65 (2H, m), 0.98 (6H,t, J=7.2 Hz), 2.47-2.59 (7H, m), 3.37 (2H, m), 4.03 (3H, s), 6.51 (1H,d, J=5.2 Hz), 7.18 (1H, d, J=2.8 Hz), 7.22 (1H, dd, J=2.8, 8.8 Hz), 7.47(1H, d, J=2.8 Hz), 7.52 (1H, s), 7.97 (1H, s), 8.25 (1H, d, J=8.8 Hz),8.48 (1H, m), 8.65 (1H, d, J=5.2 Hz), 8.69 (1H, s).

Example 402N6-(3-(1-Pyrrolidino)propyl)-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (87.0 mg, 0.162 mmol, 80.4%) was obtained as lightbrown crystals from4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid (86 mg, 0.20 mmol) and 1-(3-aminopropyl)pyrrolidine, by the sameprocedure as in Example 397.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.41 (2H, m), 0.65 (2H, m), 1.65-1.72(6H, m), 2.41-2.49 (6H, m), 2.56 (1H, m), 3.28-3.36 (2H, m), 4.01 (3H,s), 6.51 (1H, d, J=5.2 Hz), 7.18 (1H, m), 7.22 (1H, m), 7.47 (1H, d,J=2.8 Hz), 7.50 (1H, s), 7.96 (1H, s), 8.25 (1H, dd, J=1.2, 9.2 Hz),8.41 (1H, m), 8.51 (1H, s), 8.65 (1H, d, J=5.2 Hz).

Example 403N6-(2-(2-Pyridyl)ethyl)-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (78.4 mg, 0.147 mmol, 73.7%) was obtained as lightbrown crystals from4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid (86 mg, 0.20 mmol) and 2-(2-aminoethyl)pyridine, by the sameprocedure as in Example 397.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.41 (2H, m), 0.65 (2H, m), 2.56 (1H,m), 3.02 (2H, m), 3.68 (2H, m), 3.97 (3H, s), 6.51 (1H, d, J=5.2 Hz),7.18 (1H, d, J=2.8 Hz), 7.21-7.24 (2H, m), 7.32 (1H, d, J=7.6 Hz),7.47-7.49 (2H, m), 7.72 (1H, m), 7.97 (1H, s), 8.26 (1H, d, J=8.8 Hz),8.53-8.59 (3H, m), 8.65 (1H, d, J=5.2 Hz).

Example 404N6-(2-(Methylsulfonyl)ethyl)-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (58.8 mg, 0.110 mmol, 55.2%) was obtained as lightbrown crystals from4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid (86 mg, 0.20 mmol) and 2-(methylsulfonyl)ethylamine, by the sameprocedure as in Example 397.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.41 (2H, m), 0.65 (2H, m), 2.56 (1H,m), 3.06 (3H, s), 3.41 (2H, m), 3.75 (2H, m), 4.01 (3H, s), 6.51 (1H, d,J=5.2 Hz), 7.18 (1H, d, J=2.8 Hz), 7.22 (1H, dd, J=2.8, 9.2 Hz), 7.48(1H, d, J=2.8 Hz), 7.52 (1H, s), 7.97 (1H, s), 8.26 (1H, d, J=9.2 Hz),8.66 (1H, d, J=5.2 Hz), 8.67 (1H, s), 8.75 (1H, m).

Example 405N6-(1H-2-Imidazolyl)-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (27.0 mg, 0.055 mmol, 27.3%) was obtained as lightbrown crystals from4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid (86 mg, 0.20 mmol) and 2-aminoimidazole, by the same procedure asin Example 397.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.41 (2H, m), 0.65 (2H, m), 2.56 (1H,m), 4.03 (3H, s), 6.55 (1H, d, J=5.2 Hz), 6.72 (1H, m), 6.85 (1H, m),7.18 (1H, d, J=2.8 Hz), 7.24 (1H, dd, J=2.8, 8.8 Hz), 7.48 (1H, d, J=2.8Hz), 7.55 (1H, s), 7.97 (1H, s), 8.26 (1H, d, J=8.8 Hz), 8.52 (1H, s),8.68 (1H, d, J=5.2 Hz), 11.21 (1H, br), 11.80 (1H, m).

Example 406N6-(1,3-Thiazol-2-yl)-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (83.7 mg, 0.164 mmol, 81.7%) was obtained as lightbrown crystals from4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid (86 mg, 0.20 mmol) and 2-aminothiazole, by the same procedure as inExample 397.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.41 (2H, m), 0.65 (2H, m), 2.56 (1H,m), 4.03 (3H, s), 6.56 (1H, dd, J=1.6, 5.2 Hz), 7.18 (1H, s), 7.23 (1H,m), 7.30 (1H, s), 7.47-7.57 (3H, m), 7.97 (1H, s), 8.26 (1H, dd, J=1.6,8.8 Hz), 8.53 (1H, s), 8.69 (1H, dd, J=1.6, 5.2 Hz), 12.28 (1H, s).

Example 407N6-(2-Pyridyl)-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (17.0 mg, 0.034 mmol, 33.6%) was obtained as lightbrown crystals from4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid (43 mg, 0.10 mmol) and 2-aminopyridine, by the same procedure as inExample 397.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.41 (2H, m), 0.65 (2H, m), 2.56 (1H,m), 4.09 (3H, s), 6.55 (1H, d, J=5.2 Hz), 7.15-7.26 (3H, m), 7.50 (1H,s), 7.59 (1H, s), 7.86 (1H, m), 7.98 (1H, s), 8.26 (2H, d, J=9.2 Hz),8.36 (1H, m), 8.68-8.70 (2H, m), 10.70 (1H, s).

Example 408N6-(3-Pyridyl)-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (46.4 mg, 0.092 mmol, 92.1%) was obtained as lightbrown crystals from4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid (43 mg, 0.10 mmol) and 3-aminopyridine, by the same procedure as inExample 397.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.41 (2H, m), 0.65 (2H, m), 2.56 (1H,m), 4.09 (3H, s), 6.56 (1H, d, J=5.2 Hz), 7.23-7.41 (3H, m), 7.46 (1H,s), 7.57 (1H, s), 8.03 (1H, s), 8.18-8.31 (3H, m), 8.48 (1H, s), 8.68(1H, d, J=5.2 Hz), 8.80 (1H, s), 10.58 (1H, s).

Example 409N6-(4-Pyridyl)-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (31.1 mg, 0.062 mmol, 61.7%) was obtained as lightbrown crystals from4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid (43 mg, 0.10 mmol) and 4-aminopyridine, by the same procedure as inExample 397.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.41 (2H, m), 0.65 (2H, m), 2.56 (1H,m), 4.01 (3H, s), 6.56 (1H, d, J=5.2 Hz), 7.21-7.24 (2H, m), 7.47 (1H,d, J=2.8 Hz), 7.57 (1H, s), 7.71 (2H, d, J=5.6 Hz), 7.99 (1H, s), 8.26(1H, d, J=9.2 Hz), 8.44-8.48 (3H, m), 8.69 (1H, d, J=5.2 Hz), 10.73 (1H,s).

Example 410N6-(2-Hydroxyethyl)-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (34.4 mg, 0.073 mmol, 36.3) was obtained as whitecrystals from4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid (86 mg, 0.20 mmol) and 2-aminoethanol, by the same procedure as inExample 397.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.41 (2H, m), 0.65 (2H, m), 2.56 (1H,m), 3.40 (2H, m), 3.55 (2H, m), 4.03 (3H, s), 4.80 (1H, t, J=5.6 Hz),6.56 (1H, d, J=5.2 Hz), 7.20 (1H, d, J=2.8 Hz), 7.25 (1H, dd, J=2.8, 9.2Hz), 7.50 (1H, d, J=2.8 Hz), 7.53 (1H, s), 7.99 (1H, s), 8.28 (1H, d,J=9.2 Hz), 8.42 (1H, m), 8.65 (1H, s), 8.67 (1H, d, J=5.2 Hz).

Example 411N6-(3-Hydroxypropyl)-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (51.2 mg, 0.106 mmol, 52.5%) was obtained as whitecrystals from4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid (86 mg, 0.20 mmol) and 3-aminopropanol, by the same procedure as inExample 397.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.41 (2H, m), 0.65 (2H, m), 1.67 (2H,m), 2.56 (1H, m), 3.36 (2H, m), 3.50 (2H, m), 4.02 (3H, s), 4.56 (1H, t,J=5.2 Hz), 6.51 (1H, d, J=5.2 Hz), 7.18 (1H, d, J=2.8 Hz), 7.22 (1H, dd,J=2.8, 9.2 Hz), 7.47 (1H, d, J=2.8 Hz), 7.50 (1H, s), 7.97 (1H, s), 8.26(1H, d, J=9.2 Hz), 8.48 (1H, m), 8.57 (1H, s), 8.65 (1H, d, J=5.2 Hz).

Example 412N6-((2-Hydroxy-1-(hydroxymethyl)ethyl)-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

After dissolving4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid (86 mg, 0.20 mmol) in dimethylformamide (4 ml) under a nitrogenatmosphere, serinol (37 mg, 0.40 mmol), triethylamine (0.2 ml) and(1H-1,2,3-benzotriazol-1-yloxy)(tri(dimethylamino))phosphoniumhexafluorophosphate (177 mg, 0.40 mmol) were added in that order at roomtemperature, and the mixture was stirred for 8 hours. The reactionsolution was distributed between ethyl acetate and water, and theorganic layer was washed with water and saturated brine and dried overanhydrous sodium sulfate. The solvent was distilled off, andpurification was performed by silica gel column chromatography(eluent—ethyl acetate:methanol=9:1). The fraction containing the targetsubstance was concentrated under reduced pressure and suspended in ethylacetate, the suspension was diluted with hexane, and the crystals werefiltered out and blow-dried to obtain the title compound (75.8 mg, 0.151mmol, 75.3%) as white crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.42 (2H, m), 0.65 (2H, m), 2.56 (1H,m), 3.50 (2H, m), 3.56 (2H, m), 3.96 (1H, m), 4.03 (3H, s), 4.80 (2H, t,J=5.2 Hz), 6.51 (1H, d, J=5.2 Hz), 7.19 (1H, d, J=2.8 Hz), 7.23 (1H, dd,J=2.8, 9.2 Hz), 7.48 (1H, d, J=2.8 Hz), 7.53 (1H, s), 7.97 (1H, s), 8.26(1H, d, J=9.2 Hz), 8.29 (1H, m), 8.66 (1H, d, J=5.2 Hz), 8.72 (1H, s).

Example 413N6-(1,3-Dioxolan-2-ylmethyl)-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (190.3 mg, 0.371 mmol, 79.4%) was obtained as whitecrystals from4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid (200 mg, 0.467 mmol) and 2-aminomethyl-1,3-dioxolane, by the sameprocedure as in Example 412.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.41 (2H, m), 0.65 (2H, m), 2.56 (1H,m), 3.51 (2H, m), 3.85 (2H, m), 3.96 (2H, m), 4.04 (3H, s), 5.04 (1H,m), 6.51 (1H, d, J=5.2 Hz), 7.20 (1H, d, J=2.8 Hz), 7.25 (1H, dd, J=2.8,9.2 Hz), 7.49 (1H, d, J=2.8 Hz), 7.54 (1H, s), 7.99 (1H, s), 8.27 (1H,d, J=9.2 Hz), 8.48 (1H, m), 8.64 (1H, s), 8.68 (1H, d, J=5.2 Hz).

Example 414N6-(tert-Butoxy)-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (360 mg, 0.722 mmol, 72.2%) was obtained as whitecrystals from4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid (428 mg, 1.00 mmol) and tert-butoxylamine hydrochloride, by thesame procedure as in Example 412.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.42 (2H, m), 0.65 (2H, m), 1.25 (9H,s), 2.56 (1H, m), 3.97 (3H, s), 6.52 (1H, d, J=5.2 Hz), 7.18 (1H, d,J=2.8 Hz), 7.22 (1H, dd, J=2.8, 9.2 Hz), 7.47 (1H, d, J=2.8 Hz), 7.49(1H, s), 7.97 (1H, s), 8.24 (1H, s), 8.26 (1H, d, J=9.2 Hz), 8.65 (1H,d, J=5.2 Hz), 10.75 (1H, s).

Example 415N6-(2-Fluoroethyl)-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (130.7 mg, 0.276 mmol, 69.1%) was obtained as whitecrystals from4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid (171 mg, 0.40 mmol) and 2-fluoroethylamine hydrochloride, by thesame procedure as in Example 412.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.41 (2H, m), 0.65 (2H, m), 2.56 (1H,m), 3.59 (1H, m), 3.67 (1H, m), 4.03 (3H, s), 4.50 (1H, m), 4.62 (1H,m), 6.52 (1H, d, J=5.2 Hz), 7.19 (1H, d, J=2.8 Hz), 7.24 (1H, dd, J=2.8,9.2 Hz), 7.49 (1H, d, J=2.8 Hz), 7.53 (1H, s), 7.99 (1H, s), 8.28 (1H,d, J=9.2 Hz), 8.58-8.62 (2H, m), 8.67 (1H, d, J=5.2 Hz).

Example 416N6-(2-(Methylthio)ethyl)-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (146.2 mg, 0.292 mmol, 73.0%) was obtained as whitecrystals from4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid (171 mg, 0.40 mmol) and 2-(methylthio)ethylamine, by the sameprocedure as in Example 412.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.42 (2H, m), 0.65 (2H, m), 2.10 (3H,s), 2.56 (1H, m), 2.67 (2H, m), 3.50 (2H, m), 4.02 (3H, s), 6.51 (1H, d,J=5.2 Hz), 7.18 (1H, d, J=2.8 Hz), 7.22 (1H, dd, J=2.8, 9.2 Hz), 7.48(1H, d, J=2.8 Hz), 7.51 (1H, s), 7.97 (1H, s), 8.26 (1H, d, J=9.2 Hz),8.56 (1H, m), 8.61 (1H, s), 8.65 (1H, d, J=5.2 Hz).

Example 417N6-Methoxy-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (109.3 mg, 0.239 mmol, 59.9%) was obtained as whitecrystals from4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid (171 mg, 0.40 mmol) and methoxylamine hydrochloride, by the sameprocedure as in Example 412.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.42 (2H, m), 0.65 (2H, m), 2.56 (1H,m), 3.74 (3H, s), 3.99 (3H, s), 6.54 (1H, d, J=5.2 Hz), 7.20 (1H, d,J=2.8 Hz), 7.25 (1H, dd, J=2.8, 9.2 Hz), 7.48 (1H, d, J=2.8 Hz), 7.49(1H, s), 7.99 (1H, s), 8.28 (1H, d, J=9.2 Hz), 8.43 (1H, s), 8.67 (1H,d, J=5.2 Hz), 11.46 (1H, s).

Example 418N-(4-((7-(Benzyloxy)-6-cyano-4-quinolyl))oxy-2-chlorophenyl)-N′-cyclopropylurea

After dissolving4-(4-amino-3-chlorophenoxy)-7-benzyloxy-6-cyanoquinoline (8.037 g, 20.0mmol) in dimethylformamide (40 ml) under a nitrogen atmosphere, pyridine(1.94 ml, 24.0 mmol) and phenylchloroformate (3.01 ml, 24.0 mmol) wereadded dropwise at room temperature and the mixture was stirred for 1hour. Cyclopropylamine (3.46 ml, 50 mmol) was added dropwise, and themixture was further stirred for 3 hours. Water (400 ml) and diethylether (400 ml) were added to the reaction solution, and after stirringovernight, the precipitated crystals were filtered out, washed withwater and diethyl ether and dried at 70° C. to obtain the title compound(8.570 g, 17.7 mmol, 88.4%) as light brown crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.42 (2H, m), 0.65 (2H, m), 2.56 (1H,m), 5.45 (2H, s), 6.58 (1H, d, J=5.2 Hz), 7.19 (1H, d, J=2.8 Hz), 7.25(1H, dd, J=2.8, 9.2 Hz), 7.36 (1H, m), 7.44 (2H, t, J=7.2 Hz), 7.50 (1H,d, J=2.8 Hz), 7.54 (2H, d, J=7.2 Hz), 7.71 (1H, s), 7.98 (1H, s), 8.27(1H, d, J=9.2 Hz), 8.73 (1H, d, J=5.2 Hz), 8.77 (1H, s).

Example 419N-(2-Chloro-4-((6-cyano-7-(3-(diethylamino)propoxy)-4-quinolyl)oxy)phenyl)-N′-cyclopropylurea

AnN-(4-(6-cyano-7-hydroxy-4-quinolyl)oxy-2-chlorophenyl)-N′-cyclopropylureacrude product (5.67 g) was obtained as light brown crystals fromN-(4-((7-(benzyloxy)-6-cyano-4-quinolyl))oxy-2-chlorophenyl)-N′-cyclopropylurea(8.53 g, 17.6 mmol) by the same procedure as in Example 83. The titlecompound (200 mg, 0.394 mmol, 24.6%) was obtained as light yellowcrystals from the crude product (500 mg, 1.60 mmol) andN-(3-chloropropyl)-N,N-diethylamine hydrochloride, by the same procedureas in Example 7.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 0.79 (2H, m), 0.96 (2H, m), 1.05 (6H,t, J=7.2 Hz), 2.06 (2H, m), 2.52-2.60 (5H, m), 2.67-2.73 (3H, m), 4.29(2H, t, J=6.0 Hz), 5.00 (1H, s), 6.49 (1H, d, J=5.2 Hz), 7.12 (1H, dd,J=2.8, 8.8 Hz), 7.48 (1H, s), 7.72 (1H, s), 8.44 (1H, d, J=8.8 Hz), 8.66(1H, s), 8.68 (1H, d, J=5.2 Hz).

Example 420 tert-Butyl4-(((4-(3-chloro-4-((cyclopropylamino)carbonyl)aminophenoxy)-6-cyano-7-quinolyl)oxy)methyl)-1-piperidinecarboxylate

The title compound (275.8 mg, 0.466 mmol, 14.6%) was obtained as whitecrystals from anN-(4-(6-cyano-7-hydroxy-4-quinolyl)oxy-2-chlorophenyl)-N′-cyclopropylureacrude product (1.00 g, 3.20 mmol) and tert-butyl4-(bromomethyl)-1-piperidinecarboxylate, by the same procedure as inExample 7.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 0.79 (2H, m), 0.96 (2H, m), 1.33 (3H,m), 1.48 (9H, s), 1.93 (2H, m), 2.16 (1H, m), 2.68 (1H, m), 2.79 (2H,m), 4.06 (2H, d, J=6.8 Hz), 4.20 (2H, m), 4.99 (1H, s), 6.50 (1H, d,J=5.2 Hz), 7.12 (1H, dd, J=2.8, 9.2 Hz), 7.43 (1H, d, J=2.8 Hz), 7.72(1H, s), 8.44 (1H, d, J=9.2 Hz), 8.66 (1H, s), 8.68 (1H, d, J=5.2 Hz).

Example 421N-(2-Chloro-4-((6-cyano-7-(4-piperidylmethoxy)-4-quinolyl)oxy)phenyl)-N′-cyclopropylurea

After adding trifluoroacetic acid (2.5 ml) to tert-butyl4-(((4-(3-chloro-4-((cyclopropylamino)carbonyl)aminophenoxy)-6-cyano-7-quinolyl)oxy)methyl)-1-piperidinecarboxylate(501 mg, 0.846 mmol) at room temperature, the mixture was stirred for 1hour. The reaction solution was diluted with water (35 ml) while coolingin an ice water bath, and then sodium bicarbonate (3.5 g) was graduallyadded for neutralization and extraction was performed with ethylacetate. The organic layer was washed with water and saturated brine,and then dried over anhydrous sodium sulfate. The solvent was distilledoff, the residue was suspended in ethyl acetate and diluted with hexane,and the precipitated crystals were filtered out and blow-dried to obtainthe title compound (414.4 mg, 0.842 mmol, 99.6%) as white crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.41 (2H, m), 0.65 (2H, m), 1.49 (2H,m), 1.92-1.97 (3H, m), 2.48 (1H, m), 2.56 (1H, m), 2.86-2.93 (3H, m),4.19 (2H, d, J=6.0 Hz), 6.58 (1H, dd, J=1.2, 5.2 Hz), 7.20 (1H, s), 7.24(1H, d, J=9.2 Hz), 7.48 (1H, d, J=1.2 Hz), 7.63 (1H, s), 7.99 (1H, s),8.27 (1H, d, J=9.2 Hz), 8.72-8.75 (2H, m).

Example 422N-(2-Chloro-4-((6-cyano-7-((1-methyl-4-piperidyl)methoxy)-4-quinolyl)oxy)phenyl)-N′-cyclopropylurea

After dissolvingN-(2-chloro-4-((6-cyano-7-(4-piperidylmethoxy)-4-quinolyl)oxy)phenyl)-N′-cyclopropylurea(540 mg, 0.846 mmol) in tetrahydrofuran (20 ml)-methanol (20 ml), therewere added 37% aqueous formaldehyde (1 ml), acetic acid (0.10 ml, 1.69mmol) and sodium cyanoborohydride (106 mg, 1.69 mmol) at roomtemperature, and the mixture was stirred for 1 hour. The reactionsolution was distributed between ethyl acetate and saturated aqueoussodium bicarbonate, and the organic layer was washed with saturatedbrine and dried over anhydrous sodium sulfate. The solvent was distilledoff, the residue was suspended in ethyl acetate and diluted with hexane,and the crystals were filtered out and blow-dried to obtain the titlecompound (282 mg, 0.557 mmol, 65.9%) as white crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.41 (2H, m), 0.66 (2H, m), 1.39 (2H,m), 1.75-1.90 (5H, m), 2.15 (3H, s), 2.56 (1H, m), 2.79 (2H, d, J=7.2Hz), 4.14 (2H, d, J=5.6 Hz), 6.57 (1H, d, J=5.2 Hz), 7.19 (1H, d, J=2.8Hz), 7.24 (1H, dd, J=2.8, 9.2 Hz), 7.49 (1H, d, J=2.8 Hz), 7.58 (1H, s),7.98 (1H, s), 8.27 (1H, d, J=9.2 Hz), 8.71-8.75 (2H, m).

Example 423N-(4-((7-(3-Bromopropoxy)-6-cyano-4-quinolyl)oxy)-2-chlorophenyl)-N′-cyclopropylurea

The title compound (129 mg, 0.250 mmol, 15.6%) was obtained as lightbrown crystals from anN-(4-(6-cyano-7-hydroxy-4-quinolyl)oxy-2-chlorophenyl)-N′-cyclopropylureacrude product (500 mg, 1.60 mmol) and 1,3-dibromopropane, by the sameprocedure as in Example 7.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.43 (2H, m), 0.65 (2H, m), 2.37 (2H,m), 2.56 (1H, m), 3.65 (2H, m), 4.41 (2H, m), 6.60 (1H, d, J=5.2 Hz),7.20 (1H, d, J=2.8 Hz), 7.26 (1H, dd, J=2.8, 8.8 Hz), 7.51 (1H, d, J=2.8Hz), 7.65 (1H, s), 7.99 (1H, s), 8.28 (1H, d, J=8.8 Hz), 8.73-8.78 (2H,m).

Example 424N-(2-Chloro-4-(6-cyano-7-(3-(1-pyrrolidino)propoxy)-4-quinolyl)oxy)phenyl)-N′-cyclopropylurea

After dissolvingN-(4-((7-(3-bromopropoxy)-6-cyano-4-quinolyl)oxy)-2-chlorophenyl)-N′-cyclopropylurea(116 mg, 0.225 mmol) in dimethylformamide (1.2 ml), pyrrolidine (0.20ml) was added and the mixture was stirred at room temperature for 4hours. The reaction solution was distributed between ethyl acetate andwater, and the organic layer was washed with saturated brine and driedover anhydrous sodium sulfate. The solvent was distilled off, theresidue was subjected to silica gel column chromatography (eluent-ethylacetate), the fraction containing the target substance was concentrated,suspended in ethyl acetate and diluted with hexane, and the crystalswere filtered out and blow-dried to obtain the title compound (57.3 mg,0.113 mmol, 50.3%) as white crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.42 (2H, m), 0.65 (2H, m), 1.68 (4H,br), 1.99 (2H, m), 2.45-2.61 (7H, m), 4.33 (2H, m), 6.56 (1H, d, J=5.2Hz), 7.19 (1H, d, J=2.8 Hz), 7.24 (1H, dd, J=2.8, 9.2 Hz), 7.49 (1H, d,J=2.8 Hz), 7.59 (1H, s), 7.98 (1H, s), 8.27 (1H, d, J=9.2 Hz), 8.72 (1H,d, J=5.2 Hz), 8.73 (1H, s).

Example 425N-(2-Chloro-4-((6-cyano-7-((1-methyl-3-piperidyl)methoxy)-4-quinolyl)oxy)phenyl)-N′-cyclopropylurea

After dissolving4-(4-amino-3-chlorophenoxy)-6-cyano-7-((1-methyl-3-piperidyl)methoxy)quinoline(246 mg, 0.582 mmol) in dimethylformamide (6 ml) under a nitrogenatmosphere, pyridine (0.19 ml, 2.33 mmol) and phenylchloroformate (0.15ml, 1.16 mmol) were added dropwise at room temperature, and the mixturewas stirred for 1 hour. Cyclopropylamine (0.20 ml, 2.91 mmol) was addeddropwise, and the mixture was further stirred for 3 hours. The reactionsolution was distributed between ethyl acetate and saturated aqueoussodium bicarbonate, and the organic layer was washed with water andsaturated brine and dried over anhydrous sodium sulfate. The solvent wasdistilled off, the residue was suspended in methanol and diluted withwater, and the crystals were filtered out and dried at 70° C. to obtainthe title compound (198.7 mg, 0.393 mmol, 67.5%) as light yellowcrystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.41 (2H, m), 0.65 (2H, m), 1.18 (1H,m), 1.54 (1H, m), 1.68 (1H, m), 1.79 (1H, m), 1.90 (2H, m), 2.11 (1H,m), 2.17 (3H, s), 2.56 (1H, m), 2.65 (1H, m), 2.85 (1H, m), 4.18 (2H, d,J=6.4 Hz), 6.59 (1H, d, J=5.2 Hz), 7.20 (1H, d, J=2.8 Hz), 7.26 (1H, dd,J=2.8, 9.2 Hz), 7.51 (1H, s), 7.60 (1H, s), 8.00 (1H, s), 8.29 (1H, d,J=9.2 Hz), 8.74-8.76 (2H, m).

The starting material was synthesized in the following manner.

Production Example 425-14-(4-Amino-3-chlorophenoxy)-6-cyano-7-((1-methyl-3-piperidyl)methoxy)quinoline

A 4-(4-amino-3-chlorophenoxy)-6-cyano-7-hydroxyquinoline crude product(3.306 g) was obtained as light brown crystals from4-(4-amino-3-chlorophenoxy)-7-benzyloxy-6-cyanoquinoline (3.728 g, 9.28mmol), by the same procedure as in Example 83. The title compound (246mg, 0.581 mmol, 36.4%) was obtained as light brown crystals from thecrude product (500 mg, 1.60 mmol) and 3-chloromethyl-1-methylpiperidinehydrochloride, by the same procedure as in Example 7.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.25 (1H, m), 1.62-2.01 (5H, m), 2.27(1H, m), 2.33 (3H, s), 2.33 (1H, m), 2.76 (1H, m), 4.05-4.15 (4H, m),6.46 (1H, d, J=5.2 Hz), 6.86 (1H, d, J=8.8 Hz), 6.93 (1H, dd, J=2.8, 8.8Hz), 7.14 (1H, d, J=2.8 Hz), 7.43 (1H, s), 8.65-8.67 (2H, m).

Example 426 tert-Butyl4-(2-((4-(3-chloro-4-((cyclopropylamino)carbonyl)aminophenoxy)-6-cyano-7-quinolyl)oxy)ethyl)-1-piperidinecarboxylate

After dissolving tert-butyl4-(((4-(4-amino-3-chlorophenoxy)-6-cyano-7-quinolyl)oxy)ethyl)-1-piperidinecarboxylate (486.5 mg, 0.930 mmol) in dimethylformamide (5 ml) under anitrogen atmosphere, pyridine (0.170 ml, 2.09 mmol) and phenylchloroformate (0.175 ml, 1.34 mmol) were added dropwise at roomtemperature, and the mixture was stirred for 1 hour. Cyclopropylamine(0.322 ml, 4.65 mmol) was added dropwise, and the mixture was furtherstirred overnight. The reaction solution was distributed between ethylacetate and saturated aqueous sodium bicarbonate, and the organic layerwas washed with water and saturated brine and dried over anhydroussodium sulfate. The solvent was distilled off, the residue was subjectedto silica gel column chromatography (eluent-ethyl acetate), the fractioncontaining the target substance was concentrated, suspended in ethylacetate and diluted with hexane, and the crystals were filtered out andblow-dried to obtain the title compound (343 mg, 0.566 mmol, 60.8%) aslight yellow crystals.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 0.80 (2H, m), 0.95 (2H, m), 1.21-1.28(3H, m), 1.47 (9H, s), 1.77 (2H, m), 1.89 (2H, m), 2.67 (1H, m), 2.75(2H, m), 4.12 (2H, m), 4.28 (2H, m), 4.97 (1H, s), 6.50 (1H, d, J=5.2Hz), 7.12 (1H, dd, J=2.8, 8.8 Hz), 7.25 (1H, d, J=2.8 Hz), 7.45 (1H, s),7.72 (1H, s), 8.44 (1H, d, J=8.8 Hz), 8.66 (1H, s), 8.68 (1H, d, J=5.2Hz).

The starting material was synthesized in the following manner.

Production Example 426-1 tert-Butyl4-(2-(((4-amino-3-chlorophenoxy)-6-cyano-7-quinolyl)oxy)ethyl)-1-piperidinecarboxylate

The title compound (492.6 mg, 0.942 mmol, 39.6%) was obtained as lightbrown crystals from an4-(4-amino-3-chlorophenoxy)-6-cyano-7-hydroxyquinoline crude product(742 mg, 2.38 mmol) and tert-butyl 4-(bromoethyl)-1-piperidinecarboxylate, by the same procedure as in Example 7.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.11-1.31 (4H, m), 1.46 (9H, s), 1.77(2H, m), 1.90 (2H, m), 2.52-2.56 (3H, m), 4.11 (2H, m), 4.27 (2H, m),6.48 (1H, d, J=5.2 Hz), 6.86 (1H, d, J=9.2 Hz), 6.93 (1H, dd, J=2.8, 9.2Hz), 7.14 (1H, d, J=2.8 Hz), 7.44 (1H, s), 8.66-8.68 (2H, m).

Example 427N-(2-Chloro-4-((6-cyano-7-(2-(4-piperidyl)ethoxy)-4-quinolyl)oxy)phenyl)-N′-cyclopropylurea

After adding trifluoroacetic acid (3.0 ml) to tert-butyl4-(((4-(3-chloro-4-((cyclopropylamino)carbonyl)aminophenoxy)-6-cyano-7-quinolyl)oxy)ethyl)-1-piperidinecarboxylate(343 mg, 0.566 mmol) at room temperature, the mixture was stirred for 1hour. The reaction solution was diluted with water (40 ml) while coolingin an ice water bath, and then sodium bicarbonate (4.0 g) was graduallyadded for neutralization and extraction was performed with ethylacetate. The organic layer was washed with water and saturated brine,and then dried over anhydrous sodium sulfate. The solvent was distilledoff, the residue was suspended in ethyl acetate and diluted with hexane,and the precipitated crystals were filtered out and blow-dried to obtainthe title compound (286 mg, 0.566 mmol, quantitative) as light yellowcrystals.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 0.78 (2H, m), 0.95 (2H, m), 1.63 (2H,m), 1.96-2.05 (5H, m), 2.66 (1H, m), 2.90 (2H, m), 3.41 (2H, m),4.27-4.30 (3H, m), 5.10 (1H, s), 6.50 (1H, d, J=5.2 Hz), 7.12 (1H, dd,J=2.8, 8.8 Hz), 7.27 (1H, d, J=2.8 Hz), 7.46 (1H, s), 7.73 (1H, s), 8.44(1H, d, J=8.8 Hz), 8.66 (1H, s), 8.68 (1H, d, J=5.2 Hz).

Example 428N-(2-Chloro-4-((6-cyano-7-(2-(1-methyl-4-piperidyl)ethoxy)-4-quinolyl)oxy)phenyl)-N′-cyclopropylurea

After dissolvingN-(2-chloro-4-((6-cyano-7-(2-(4-piperidylethoxy))-4-quinolyl)oxy)phenyl)-N′-cyclopropylurea(286 mg, 0.566 mmol) in tetrahydrofuran (5 ml)-methanol (5 ml), therewere added 37% aqueous formaldehyde (0.5 ml), acetic acid (0.065 ml,1.13 mmol) and sodium cyanoborohydride (71 mg, 1.13 mmol) at roomtemperature, and the mixture was stirred for 1 hour. The reactionsolution was distributed between ethyl acetate and saturated aqueoussodium bicarbonate, and the organic layer was washed with saturatedbrine and dried over anhydrous sodium sulfate. The solvent was distilledoff, the residue was suspended in ethyl acetate and diluted with hexane,and the crystals were filtered out and blow-dried to obtain the titlecompound (218.2 mg, 0.420 mmol, 74.1%) as light yellow crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.41 (2H, m), 0.65 (2H, m), 1.23 (2H,m), 1.50 (1H, m), 1.71-1.88 (6H, m), 2.15 (3H, s), 2.56 (1H, m), 2.75(2H, m), 4.33 (2H, t, J=6.4 Hz), 6.58 (1H, d, J=5.2 Hz), 7.20 (1H, d,J=2.8 Hz), 7.26 (1H, dd, J=2.8, 9.2 Hz), 7.50 (1H, d, J=2.8 Hz), 7.62(1H, s), 8.00 (1H, s), 8.28 (1H, d, J=9.2 Hz), 8.73-8.75 (2H, m).

Example 429N-(2-Chloro-4-((6-cyano-7-(((2R)-3-(diethylamino)-2-hydroxypropyl)oxy)-4-quinolyl)oxy)phenyl)-N′-cyclopropylurea

After dissolving(4-(4-amino-3-chlorophenoxy)-6-cyano-7-(((2R)-3-(diethylamino)-2-hydroxypropyl)oxy)quinoline)(96.9 mg, 0.22 mmol) in dimethylformamide (1 ml) under a nitrogenatmosphere, pyridine (0.027 ml, 0.33 mmol) and phenyl chloroformate(0.035 ml, 0.28 mmol) were added dropwise at room temperature, and themixture was stirred for 1 hour. Cyclopropylamine (0.10 ml) was addeddropwise, and the mixture was further stirred overnight. The reactionsolution was distributed between ethyl acetate and saturated aqueoussodium bicarbonate, and the organic layer was washed with water andsaturated brine and dried over anhydrous sodium sulfate. The solvent wasdistilled off, the residue was subjected to silica gel columnchromatography (eluent-ethyl acetate), the fraction containing thetarget substance was concentrated, suspended in ethyl acetate anddiluted with hexane, and the crystals were filtered out and blow-driedto obtain the title compound (61.6 mg, 0.118 mmol, 53.5%) as lightyellow crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.42 (2H, m), 0.65 (2H, m), 0.96 (6H,t, J=7.2 Hz), 2.42-2.67 (7H, m), 3.95 (1H, m), 4.21 (1H, m), 4.30 (1H,m), 4.91 (1H, m), 6.57 (1H, d, J=5.2 Hz), 7.19 (1H, d, J=2.8 Hz), 7.25(1H, dd, J=2.8, 9.2 Hz), 7.50 (1H, d, J=2.8 Hz), 7.61 (1H, s), 7.98 (1H,s), 8.27 (1H, d, J=9.2 Hz), 8.70 (1H, s), 8.72 (1H, d, J=5.2 Hz).

The starting materials were synthesized in the following manner.

Production Example 429-14-(4-Amino-3-chlorophenoxy)-6-cyano-7-((2R)-oxiran-2-yl)methoxyquinoline

The title compound (198 mg, 0.538 mmol, 16.8%) was obtained as lightbrown crystals from an4-(4-amino-3-chlorophenoxy)-6-cyano-7-hydroxyquinoline crude product(1.00 g, 3.21 mmol) and (2R)-oxiran-2-ylmethyl4-methyl-1-benzenesulfonate, by the same procedure as in Example 7.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 2.93 (1H, m), 2.98 (1H, m), 3.50 (1H,m), 4.12 (2H, m), 4.24 (1H, dd, J=5.2, 11.2 Hz), 4.49 (1H, dd, J=2.8,11.2 Hz), 6.49 (1H, d, J=5.2 Hz), 6.86 (1H, d, J=8.8 Hz), 6.93 (1H, dd,J=2.8, 8.8 Hz), 7.14 (1H, d, J=2.8 Hz), 7.48 (1H, s), 8.66-8.68 (2H, m).

Production Example 429-24-(4-Amino-3-chlorophenoxy)-6-cyano-7-(((2R)-3-(diethylamino)-2-hydroxypropyl)oxy)quinoline

After dissolving4-(4-amino-3-chlorophenoxy)-6-cyano-7-((2R)-oxiran-2-yl)methoxyquinoline(96 mg, 0.261 mmol) in tetrahydrofuran (2.6 ml) under a nitrogenatmosphere, diethylamine (0.5 ml) was added and the mixture was stirredat 50° C. for 5 days. The reaction solution was concentrated underreduced pressure, the residue was subjected to silica gel columnchromatography (eluent-ethyl acetate), the fraction containing thetarget substance was concentrated, suspended in ethyl acetate anddiluted with hexane, and the crystals were filtered out and blow-driedto obtain the title compound (96.9 mg, 0.220 mmol, 84.2%) as lightyellow crystals.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.09 (6H, t, J=7.2 Hz), 2.57-2.74 (8H,m), 4.12 (2H, m), 4.25 (2H, d, J=4.8 Hz), 6.48 (1H, d, J=5.2 Hz), 6.85(1H, d, J=8.8 Hz), 6.93 (1H, dd, J=2.8, 8.8 Hz), 7.14 (1H, d, J=2.8 Hz),7.49 (1H, s), 8.66-8.68 (2H, m).

Example 430N-(2-Chloro-4-((6-cyano-7-(((2S)-3-(diethylamino)-2-hydroxypropyl)oxy)-4-quinolyl)oxy)phenyl)-N′-cyclopropylurea

After dissolving4-(4-amino-3-chlorophenoxy)-6-cyano-7-(((2S)-3-(diethylamino)-2-hydroxypropyl)oxy)quinoline(78.6 mg, 0.18 mmol) in dimethylformamide (1 ml) under a nitrogenatmosphere, pyridine (0.022 ml, 0.27 mmol) and phenyl chloroformate(0.028 ml, 0.22 mmol) were added dropwise at room temperature, and themixture was stirred for 1 hour. Cyclopropylamine (0.10 ml) was addeddropwise, and the mixture was further stirred overnight. The reactionsolution was distributed between ethyl acetate and saturated aqueoussodium bicarbonate, and the organic layer was washed with water andsaturated brine and dried over anhydrous sodium sulfate. The solvent wasdistilled off, the residue was subjected to silica gel columnchromatography (eluent-ethyl acetate), the fraction containing thetarget substance was concentrated, suspended in ethyl acetate anddiluted with hexane, and the crystals were filtered out and blow-driedto obtain the title compound (37.8 mg, 0.072 mmol, 40.5%) as lightyellow crystals.

The starting materials were synthesized in the following manner.

Production Example 430-14-(4-Amino-3-chlorophenoxy)-6-cyano-7-((2S)-oxiran-2-yl)methoxyquinoline

The title compound (147 mg, 0.400 mmol, 12.5%) was obtained as lightbrown crystals from a4-(4-amino-3-chlorophenoxy)-6-cyano-7-hydroxyquinoline crude product(1.00 g, 3.21 mmol) and (2S)-oxiran-2-ylmethyl4-methyl-1-benzenesulfonate, by the same procedure as in Example 7.

Production Example 430-24-(4-Amino-3-chlorophenoxy)-6-cyano-7-(((2S)-3-(diethylamino)-2-hydroxypropyl)oxy)quinoline

After dissolving4-(4-amino-3-chlorophenoxy)-6-cyano-7-((2S)-oxiran-2-yl)methoxyquinoline(72 mg, 0.196 mmol) in tetrahydrofuran (2.0 ml) under a nitrogenatmosphere, diethylamine (0.4 ml) was added and the mixture was stirredat 50° C. for 5 days. The reaction solution was concentrated underreduced pressure, the residue was subjected to silica gel columnchromatography (eluent-ethyl acetate), the fraction containing thetarget substance was concentrated, suspended in ethyl acetate anddiluted with hexane, and the crystals were filtered out and blow-driedto obtain the title compound (78.6 mg, 0.178 mmol, 91.1%) as lightyellow crystals.

Example 431N-(2-Chloro-4-((6-cyano-7-(((2R)-2-hydroxy-3-(1-pyrrolidino)propyl)oxy)-4-quinolyl)oxy)phenyl)-N′-cyclopropylurea

After dissolving4-(4-amino-3-chlorophenoxy)-6-cyano-7-(((2R)-2-hydroxy-3-(1-pyrrolidino)propyl)oxy)quinoline(95.1 mg, 0.217 mmol) in dimethylformamide (1 ml) under a nitrogenatmosphere, pyridine (0.026 ml, 0.33 mmol) and phenyl chloroformate(0.034 ml, 0.27 mmol) were added dropwise at room temperature, and themixture was stirred for 1 hour. Cyclopropylamine (0.10 ml) was addeddropwise, and the mixture was further stirred overnight. The reactionsolution was distributed between ethyl acetate and saturated aqueoussodium bicarbonate, and the organic layer was washed with water andsaturated brine and dried over anhydrous sodium sulfate.

The solvent was distilled off, the residue was subjected to silica gelcolumn chromatography (eluent-ethyl acetate), the fraction containingthe target substance was concentrated, suspended in ethyl acetate anddiluted with hexane, and the crystals were filtered out and blow-driedto obtain the title compound (40.3 mg, 0.077 mmol, 35.6%) as lightyellow crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.44 (2H, m), 0.68 (2H, m), 1.69 (4H,br), 2.50-2.75 (7H, m), 4.02 (1H, m), 4.22 (1H, dd, J=5.6, 10.4 Hz),4.31 (1H, dd, J=3.6, 10.4 Hz), 5.04 (1H, m), 6.59 (1H, d, J=5.2 Hz),7.21 (1H, d, J=2.8 Hz), 7.27 (1H, dd, J=2.8, 9.2 Hz), 7.52 (1H, d, J=2.8Hz), 7.63 (1H, s), 7.99 (1H, s), 8.29 (1H, d, J=9.2 Hz), 8.72-8.74 (2H,m).

Production Example 431-14-(4-Amino-3-chlorophenoxy)-6-cyano-7-(((2R)-2-hydroxy-3-(1-pyrrolidino)propyl)oxy)quinoline

After dissolving4-(4-amino-3-chlorophenoxy)-6-cyano-7-((2R)-oxiran-2-yl)methoxyquinoline(96 mg, 0.261 mmol) in tetrahydrofuran (2.0 ml) under a nitrogenatmosphere, pyrrolidine (0.2 ml) was added and the mixture was stirredat room temperature for 5 days. The reaction solution was concentratedunder reduced pressure, the residue was subjected to silica gel columnchromatography (eluent-ethyl acetate), the fraction containing thetarget substance was concentrated, suspended in ethyl acetate anddiluted with hexane, and the crystals were filtered out and blow-driedto obtain the title compound (95.5 mg, 0.218 mmol, 83.4%) as lightyellow crystals.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.26 (2H, m), 1.82 (4H, br), 2.58-2.76(5H, m), 2.94 (1H, m), 4.11 (2H, m), 4.20-4.45 (2H, m), 6.48 (1H, d,J=5.2 Hz), 6.85 (1H, d, J=8.8 Hz), 6.93 (1H, dd, J=2.8, 8.8 Hz), 7.14(1H, d, J=2.8 Hz), 7.49 (1H, s), 8.66-8.68 (2H, m).

Example 432N-(2-Chloro-4-((6-cyano-7-(((2S)-2-hydroxy-3-(1-pyrrolidino)propyl)oxy)-4-quinolyl)oxy)phenyl)-N′-cyclopropylurea

After dissolving4-(4-amino-3-chlorophenoxy)-6-cyano-7-(((2R)-2-hydroxy-3-(1-pyrrolidino)propyl)oxy)quinoline(82.0 mg, 0.187 mmol) in dimethylformamide (1 ml) under a nitrogenatmosphere, pyridine (0.023 ml, 0.28 mmol) and phenyl chloroformate(0.029 ml, 0.23 mmol) were added dropwise at room temperature and themixture was stirred for 1 hour. Cyclopropylamine (0.10 ml) was addeddropwise, and the mixture was further stirred overnight. The reactionsolution was distributed between ethyl acetate and saturated aqueoussodium bicarbonate, and the organic layer was washed with water andsaturated brine and dried over anhydrous sodium sulfate. The solvent wasdistilled off, the residue was subjected to silica gel columnchromatography (eluent-ethyl acetate), the fraction containing thetarget substance was concentrated, suspended in ethyl acetate anddiluted with hexane, and the crystals were filtered out and blow-driedto obtain the title compound (25.0 mg, 0.048 mmol, 25.6%) as lightyellow crystals.

Production Example 432-14-(4-Amino-3-chlorophenoxy)-6-cyano-7-(((2S)-2-hydroxy-3-(1-pyrrolidino)propyl)oxy)quinoline

After dissolving4-(4-amino-3-chlorophenoxy)-6-cyano-7-((2S)-oxiran-2-yl)methoxyquinoline(72 mg, 0.196 mmol) in tetrahydrofuran (1.5 ml) under a nitrogenatmosphere, pyrrolidine (0.15 ml) was added and the mixture was stirredat room temperature for 5 days. The reaction solution was concentratedunder reduced pressure, the residue was subjected to silica gel columnchromatography (eluent-ethyl acetate), the fraction containing thetarget substance was concentrated, suspended in ethyl acetate anddiluted with hexane, and the crystals were filtered out and blow-driedto obtain the title compound (82.0 mg, 0.187 mmol, 95.4%) as lightyellow crystals.

Example 433 Methyl4-(4-(((4-fluoroanilino)carbonyl)(methyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylate

The title compound (1.078 g, 2.27 mmol, 92.6%) was obtained as whitecrystals from methyl7-methoxy-4-(4-(methylamino)phenoxy)quinolinecarboxylate (828 mg, 2.45mmol) and 4-fluorophenyl isocyanate, by the same procedure as in Example10.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.39 (3H, s), 3.98 (3H, s), 4.06 (3H,s), 6.20 (1H, s), 6.57 (1H, d, J=5.2 Hz), 6.97 (2H, m), 7.24-7.34 (4H,m), 7.46 (2H, m), 7.52 (1H, s), 8.71 (1H, d, J=5.2 Hz), 8.78 (1H, s).

The starting material was synthesized in the following manner.

Production Example 433-1 Methyl7-methoxy-4-(4-(methylamino)phenoxy)-6-quinolinecarboxylate

After dissolving 4-methylaminophenol (1.11 g, 9.00 mmol) indimethylsulfoxide (15 ml), sodium hydride (360 mg, 9.00 mmol) wasgradually added at room temperature and the mixture was stirred for 20minutes. 4-Chloro-7-methoxy-6-methoxycarbonylquinoline (1.51 g, 6.00mmol) obtained by a publicly known method was added, and the mixture washeated at 100° C. for 2 hours while stirring. Upon cooling to roomtemperature, the reaction solution was distributed between ethyl acetateand water, and the organic layer was washed with water and saturatedbrine and dried over anhydrous sodium sulfate. The solvent was distilledoff and subjected to silica gel column chromatography (eluent-ethylacetate), the fraction containing the target substance was concentrated,suspended in ethyl acetate and diluted with hexane, and the crystalswere filtered out and blow-dried to obtain the title compound (830 mg,2.45 mmol, 40.9%) as light yellow crystals.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 2.88 (3H, s), 3.83 (1H, br), 3.97 (3H,s), 4.04 (3H, s), 6.42 (1H, d, J=5.2 Hz), 6.68 (2H, d, J=8.8 Hz), 7.01(2H, d, J=8.8 Hz), 7.45 (1H, s), 8.60 (1H, d, J=5.2 Hz), 8.84 (1H, s).

Example 4344-(4-(((4-Fluoroanilino)carbonyl)(methyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid

After adding methanol (20 ml) and 2N aqueous sodium hydroxide (5 ml) tomethyl4-(4-(((4-fluoroanilino)carbonyl)(methyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylate(1.042 g, 2.19 mmol), the mixture was stirred at room temperature for 3hours. 2N Hydrochloric acid was added to the reaction solution forneutralization, and then the methanol was distilled off under reducedpressure and the precipitated white crystals were filtered out and driedat 70° C. to obtain the title compound (1.01 g, 2.19 mmol,quantitative).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.29 (3H, s), 3.96 (3H, s), 6.64 (1H,d, J=5.2 Hz), 7.06 (2H, t, J=8.8 Hz), 7.33 (2H, d, J=8.8 Hz), 7.42-7.50(5H, m), 8.23 (1H, s), 8.54 (1H, s), 8.70 (1H, d, J=5.2 Hz), 13.09 (1H,br).

Example 435N6-Cyclopropyl-4-(4-(((4-fluoroanilino)carbonyl)(methyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

After dissolving4-(4-(((4-fluoroanilino)carbonyl)(methyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid (115 mg, 0.25 mmol) in dimethylformamide (2 ml) under a nitrogenatmosphere, triethylamine (0.2 ml),(1H-1,2,3-benzotriazol-1-yloxy)(tri(dimethylamino))phosphoniumhexafluorophosphate (221 mg, 0.50 mmol) and cyclopropylamine (0.10 ml)were added in that order at room temperature, and the mixture wasstirred overnight. The reaction solution was distributed between ethylacetate and water, and the organic layer was washed with water andsaturated brine and dried over anhydrous sodium sulfate. The solvent wasdistilled off, and purification was performed by silica gel columnchromatography (eluent-ethyl acetate). The fraction containing thetarget substance was concentrated under reduced pressure and suspendedin ethyl acetate, the suspension was diluted with hexane, and thecrystals were filtered out and blow-dried to obtain the title compound(78.7 mg, 0.157 mmol, 63.1%) as white crystals. ¹H-NMR Spectrum(DMSO-d₆) δ (ppm): 0.57 (2H, m), 0.70 (2H, m), 2.86 (1H, m), 3.29 (3H,s), 3.98 (3H, s), 6.64 (1H, d, J=5.2 Hz), 7.06 (2H, t, J=8.8 Hz), 7.31(2H, d, J=8.8 Hz), 7.42-7.49 (5H, m), 8.23 (1H, s), 8.34 (1H, d, J=4.0Hz), 8.43 (1H, s), 8.68 (1H, d, J=5.2 Hz).

Example 436N6-(2-Methoxyethyl)-4-(4-(((4-fluoroanilino)carbonyl)(methyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (97.0 mg, 0.187 mmol, 75.1%) was obtained as whitecrystals from 4-(4-(((4-fluoroanilino)carbonyl)(methyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylic acid(115 mg, 0.25 mmol) and 2-methoxyethylamine, by the same procedure as inExample 435.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.29 (3H, s), 3.30 (3H, s), 3.48 (4H,br), 4.02 (3H, s), 6.65 (1H, d, J=5.2 Hz), 7.06 (2H, t, J=8.8 Hz), 7.32(2H, d, J=8.8 Hz), 7.43-7.48 (4H, m), 7.52 (1H, s), 8.23 (1H, s), 8.45(1H, br), 8.62 (1H, s), 8.69 (1H, d, J=5.2 Hz).

Example 437N6-Methoxy-4-(4-(((4-fluoroanilino)carbonyl)(methyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (79.2 mg, 0.161 mmol, 64.8%) was obtained as whitecrystals from4-(4-(((4-fluoroanilino)carbonyl)(methyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid (115 mg, 0.25 mmol) and methoxylamine hydrochloride, by the sameprocedure as in Example 435.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.29 (3H, s), 3.73 (3H, s), 3.98 (3H,s), 6.65 (1H, d, J=5.2 Hz), 7.06 (2H, t, J=8.8 Hz), 7.32 (2H, d, J=8.8Hz), 7.42-7.50 (5H, m), 8.23 (1H, s), 8.44 (1H, s), 8.69 (1H, d, J=5.2Hz), 11.45 (1H, s).

Example 438N6-(2-Ethoxyethyl)-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

After dissolving4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid (86 mg, 0.20 mmol) in dimethylformamide (2 ml) under a nitrogenatmosphere, 2-ethoxyethylamine (0.042 ml, 0.40 mmol), triethylamine (0.2ml) and ((1H-1,2,3-benzotriazol-1-yloxy)(tri(dimethylamino))phosphoniumhexafluorophosphate) (133 mg, 0.20 mmol) were added in that order atroom temperature, and the mixture was stirred overnight. The reactionsolution was distributed between ethyl acetate and water, and theorganic layer was washed with water and saturated brine and dried overanhydrous sodium sulfate. The solvent was distilled off and suspended inethyl acetate, the suspension was diluted with hexane, and the crystalswere filtered out and blow-dried to obtain the title compound (87.7 mg,0.176 mmol, 87.9%) as white crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.42 (2H, m), 0.64 (2H, m), 1.13 (3H,t, J=6.8 Hz), 2.56 (1H, m), 3.44-3.53 (6H, m), 4.02 (3H, s), 6.52 (1H,d, J=5.2 Hz), 7.18 (1H, d, J=2.8 Hz), 7.22 (1H, dd, J=2.8, 9.2 Hz), 7.48(1H, d, J=2.8 Hz), 7.52 (1H, s), 7.97 (1H, s), 8.25 (1H, s), 8.26 (1H,dd, J=2.8, 9.2 Hz), 8.46 (1H, m), 8.62 (1H, s), 8.66 (1H, d, J=5.2 Hz).

Example 439N6-(2-(2-Propoxy)ethyl)-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (90.0 mg, 0.175 mmol, 87.7%) was obtained as whitecrystals from4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid (86 mg, 0.20 mmol) and 2-(2-propoxy)ethylamine, by the sameprocedure as in Example 438.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.42 (2H, m), 0.65 (2H, m), 1.11 (6H,d, J=6.4 Hz), 2.56 (1H, m), 3.43-3.53 (4H, m), 3.60 (1H, m), 4.02 (3H,s), 6.52 (1H, d, J=5.2 Hz), 7.18 (1H, d, J=2.8 Hz), 7.22 (1H, dd, J=2.8,8.8 Hz), 7.47 (1H, d, J=2.8 Hz), 7.52 (1H, s), 7.97 (1H, s), 8.26 (1H,d, J=8.8 Hz), 8.43 (1H, m), 8.46 (1H, s), 8.66 (1H, d, J=5.2 Hz).

Example 440N6-(2-Cyanoethyl)-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (73.8 mg, 0.154 mmol, 76.5%) was obtained as whitecrystals from4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid (86 mg, 0.20 mmol) and 3-aminopropionitrile, by the same procedureas in Example 438.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.42 (2H, m), 0.65 (2H, m), 2.56 (1H,m), 2.81 (2H, m), 3.56 (2H, m), 4.02 (3H, s), 6.53 (1H, d, J=5.2 Hz),7.20 (1H, d, J=2.8 Hz), 7.24 (1H, dd, J=2.8, 8.8 Hz), 7.49 (1H, d, J=2.8Hz), 7.53 (1H, s), 7.99 (1H, s), 8.27 (1H, d, J=8.8 Hz), 8.61 (1H, s),8.67 (1H, d, J=5.2 Hz), 8.74 (1H, m).

Example 441N6-Cyanomethyl-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (82.7 mg, 0.178 mmol, 88.8%) was obtained as whitecrystals from4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid (86 mg, 0.20 mmol) and 2-aminoacetonitrile hydrochloride, by thesame procedure as in Example 438.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.42 (2H, m), 0.65 (2H, m), 2.56 (1H,m), 4.05 (3H, s), 4.35 (2H, d, J=5.6 Hz), 6.54 (1H, d, J=5.2 Hz), 7.20(1H, d, J=2.8 Hz), 7.25 (1H, dd, J=2.8, 9.2 Hz), 7.50 (1H, d, J=2.8 Hz),7.56 (1H, s), 7.99 (1H, s), 8.28 (1H, d, J=9.2 Hz), 8.69 (1H, d, J=5.2Hz), 8.71 (1H, s), 9.05 (1H, m).

Example 442N6-Methyl-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (31.6 mg, 0.072 mmol, 71.7%) was obtained as whitecrystals from4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid (43 mg, 0.10 mmol) and 40% methylamine (methanol solution), by thesame procedure as in Example 438.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.42 (2H, m), 0.65 (2H, m), 2.56 (1H,m), 2.82 (3H, d, J=4.8 Hz), 4.00 (3H, s), 6.51 (1H, d, J=5.2 Hz), 7.18(1H, d, J=2.8 Hz), 7.22 (1H, dd, J=2.8, 9.2 Hz), 7.47 (1H, d, J=2.8 Hz),7.50 (1H, s), 7.96 (1H, s), 8.26 (1H, d, J=9.2 Hz), 8.34 (1H, m), 8.57(1H, s), 8.65 (1H, d, J=5.2 Hz).

Example 443N6-Ethyl-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (29.6 mg, 0.065 mmol, 65.1%) was obtained as whitecrystals from4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid (43 mg, 0.10 mmol) and 2.0 Methylamine (tetrahydrofuran solution),by the same procedure as in Example 438.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.42 (2H, m), 0.65 (2H, m), 1.13 (3H,t, J=7.2 Hz), 2.56 (1H, m), 3.25-3.35 (2H, m), 4.00 (3H, s), 6.51 (1H,d, J=5.2 Hz), 7.18 (1H, d, J=2.8 Hz), 7.21 (1H, dd, J=2.8, 9.2 Hz), 7.46(1H, d, J=2.8 Hz), 7.49 (1H, s), 7.96 (1H, s), 8.25 (1H, d, J=9.2 Hz),8.37 (1H, m), 8.52 (1H, s), 8.64 (1H, d, J=5.2 Hz).

Example 444N6-Propyl-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (21.6 mg, 0.046 mmol, 46.1%) was obtained as whitecrystals from4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid (43 mg, 0.10 mmol) and propylamine, by the same procedure as inExample 438.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.42 (2H, m), 0.65 (2H, m), 0.90 (3H,t, J=7.2 Hz), 1.54 (2H, m), 2.56 (1H, m), 3.22-3.28 (2H, m), 4.00 (3H,s), 6.51 (1H, d, J=5.2 Hz), 7.18 (1H, d, J=2.8 Hz), 7.21 (1H, dd, J=2.8,9.2 Hz), 7.46 (1H, d, J=2.8 Hz), 7.49 (1H, s), 7.97 (1H, s), 8.27 (1H,d, J=9.2 Hz), 8.35 (1H, m), 8.49 (1H, s), 8.64 (1H, d, J=5.2 Hz).

Example 445N6-Propargyl-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (25.4 mg, 0.055 mmol, 54.6%) was obtained as a whitepowder from4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid (43 mg, 0.10 mmol) and propargylamine, by the same procedure as inExample 438.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.42 (2H, m), 0.65 (2H, m), 2.56 (1H,m), 3.13 (1H, m), 4.00 (3H, s), 4.10 (2H, m), 6.53 (1H, d, J=5.2 Hz),7.19 (1H, d, J=2.8 Hz), 7.24 (1H, dd, J=2.8, 9.2 Hz), 7.49 (1H, d, J=2.8Hz), 7.53 (1H, s), 7.99 (1H, s), 8.27 (1H, d, J=9.2 Hz), 8.59 (1H, s),8.67 (1H, d, J=5.2 Hz), 8.79 (1H, m).

Example 446N6-Cyclopropylmethyl-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (25.6 mg, 0.053 mmol, 53.2%) was obtained as whitecrystals from4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid (43 mg, 0.10 mmol) and (aminomethyl)cyclopropane hydrochloride, bythe same procedure as in Example 438.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.26 (2H, m), 0.41-0.47 (4H, m), 0.65(2H, m), 1.06 (1H, m), 2.56 (1H, m), 3.22 (2H, m), 4.03 (3H, s), 6.53(1H, d, J=5.2 Hz), 7.19 (1H, d, J=2.8 Hz), 7.24 (1H, dd, J=2.8, 9.2 Hz),7.48 (1H, d, J=2.8 Hz), 7.52 (1H, s), 7.98 (1H, s), 8.27 (1H, d, J=9.2Hz), 8.45 (1H, m), 8.56 (1H, s), 8.67 (1H, d, J=5.2 Hz).

Example 447N6-(Cis-2-fluorocyclopropyl)-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (38.4 mg, 0.079 mmol, 79.2%) was obtained as whitecrystals from4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid (43 mg, 0.10 mmol) and cis-2-fluorocyclopropylamine tosylate, bythe same procedure as in Example 438.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.42 (2H, m), 0.65 (2H, m), 1.03-1.17(2H, m), 2.56 (1H, m), 2.91 (1H, m), 4.00 (3H, s), 4.79 (1H, m), 6.51(1H, d, J=5.2 Hz), 7.20 (1H, d, J=2.8 Hz), 7.24 (1H, dd, J=2.8, 8.8 Hz),7.47 (1H, d, J=2.8 Hz), 7.51 (1H, s), 7.98 (1H, s), 8.26 (1H, d, J=8.8Hz), 8.45 (1H, m), 8.50 (1H, s), 8.65 (1H, d, J=5.2 Hz).

Example 448N6-(3-Methoxypropyl)-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (30.3 mg, 0.061 mmol, 60.7%) was obtained as whitecrystals from4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid (43 mg, 0.10 mmol) and 3-methoxypropylamine, by the same procedureas in Example 438.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.42 (2H, m), 0.65 (2H, m), 1.77 (2H,m), 2.56 (1H, m), 3.24 (3H, s), 3.34-3.42 (4H, m), 4.00 (3H, s), 6.51(1H, d, J=5.2 Hz), 7.20 (1H, d, J=2.8 Hz), 7.24 (1H, dd, J=2.8, 9.2 Hz),7.47 (1H, d, J=2.8 Hz), 7.50 (1H, s), 7.96 (1H, s), 8.27 (1H, dd, J=2.8,9.2 Hz), 8.41 (1H, m), 8.54 (1H, s), 8.65 (1H, d, J=5.2 Hz).

Example 449N6-(2-Amino-2-oxoethyl)-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (37.4 mg, 0.077 mmol, 77.3%) was obtained as whitecrystals from4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid (43 mg, 0.10 mmol) and glycinamide hydrochloride, by the sameprocedure as in Example 438.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.42 (2H, m), 0.65 (2H, m), 2.56 (1H,m), 3.94 (2H, d, J=5.6 Hz), 4.07 (3H, s), 6.53 (1H, d, J=5.2 Hz), 7.14(1H, s), 7.20 (1H, d, J=2.8 Hz), 7.24 (1H, dd, J=2.8, 9.2 Hz), 7.44 (1H,s), 7.50 (1H, d, J=2.8 Hz), 7.56 (1H, s), 7.99 (1H, s), 8.27 (1H, d,J=9.2 Hz), 8.67-8.71 (2H, m), 8.77 (1H, s).

Example 450N6-((2R)Tetrahydro-2-furanylmethyl)-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (31.8 mg, 0.062 mmol, 62.2%) was obtained as a whitepowder from4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid (43 mg, 0.10 mmol) and R-tetrahydrofurfurylamine, by the sameprocedure as in Example 438.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.42 (2H, m), 0.65 (2H, m), 1.62 (1H,m), 1.78-1.93 (3H, m), 2.57 (1H, m), 3.38 (2H, m), 3.64 (1H, dd, J=3.6,14.0 Hz), 3.79 (1H, dd, J=4.0, 14.0 Hz), 3.99 (1H, m), 4.02 (3H, s),6.51 (1H, d, J=5.2 Hz), 7.18 (1H, s), 7.23 (1H, dd, J=2.8, 8.8 Hz), 7.47(1H, d, J=2.8 Hz), 7.52 (1H, s), 7.97 (1H, s), 8.26 (1H, d, J=8.8 Hz),8.41 (1H, m), 8.59 (1H, s), 8.65 (1H, d, J=5.2 Hz).

Example 451N6-((2S)Tetrahydro-2-furanylmethyl)-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (36.4 mg, 0.071 mmol, 71.2%) was obtained as a whitepowder from4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid (43 mg, 0.10 mmol) and S-tetrahydrofurfurylamine, by the sameprocedure as in Example 438.

Example 452N-(4-(6-Cyano-7-hydroxy-4-quinolyl)oxyphenyl)-N′-(4-fluorophenyl)urea

After dissolvingN-(4-(7-(benzyloxy)-6-cyano-4-quinolyl)oxyphenyl)-N′-(4-fluorophenyl)urea(6.20 g, 12.3 mmol) in trifluoroacetic acid (60 ml) and thioanisole (3.6ml, 30.7 mmol) under a nitrogen atmosphere, the solution was stirred at60° C. overnight. The reaction solution was concentrated under reducedpressure, and after adding water (100 ml) to the obtained residue,sodium bicarbonate was added to neutralization, diethyl ether (200 ml)was added, the mixture was stirred, and the precipitated crystals werefiltered out, washed with water and diethyl ether and dried at 70° C. toobtain the title compound (4.816 g, 11.6 mmol, 94.8%) as yellowcrystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 6.42 (1H, d, J=5.2 Hz), 7.11 (2H, m),7.22 (2H, m), 7.41 (1H, s), 7.46 (2H, m), 7.58 (2H, m), 8.64 (1H, d,J=5.2 Hz), 8.67 (1H, s), 8.73 (1H, s), 8.82 (1H, s).

Example 453N-(4-(6-Cyano-7-((2R)-oxiran-2-yl)methoxy-4-quinolyl)oxyphenyl)-N′-(4-fluorophenyl)urea

The title compound (713 mg, 1.52 mmol, 50.5%) was obtained as lightyellow crystals fromN-(4-(6-cyano-7-hydroxy-4-quinolyl)oxyphenyl)-N′-(4-fluorophenyl)urea(1.24 g, 3.0 mmol) and (2R)-oxiran-2-ylmethyl4-methyl-1-benzenesulfonate, by the same procedure as in Example 7.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.81 (1H, m), 2.92 (1H, m), 3.46 (1H,m), 4.17 (1H, dd, J=6.8, 11.6 Hz), 4.71 (1H, dd, J=2.4, 11.6 Hz), 6.53(1H, d, J=5.2 Hz), 7.12 (2H, m), 7.24 (2H, m), 7.46 (2H, m), 7.58 (2H,m), 7.63 (1H, s), 8.71-8.73 (2H, m), 8.78 (1H, s), 8.83 (1H, s).

Example 454N-(4-((6-Cyano-7-(((2R)-2-hydroxy-3-(1-pyrrolidino)propyl)oxy)-4-quinolyl)oxy)phenyl)-N′-(4-fluorophenyl)urea

After dissolvingN-(4-(6-cyano-7-((2R)-oxiran-2-yl)methoxy-4-quinolyl)oxyphenyl)-N′-(4-fluorophenyl)urea(200 mg, 0.425 mmol) in tetrahydrofuran (5.0 ml) under a nitrogenatmosphere, pyrrolidine (0.5 ml) was added and the mixture was stirredovernight at room temperature. The reaction solution was concentratedunder reduced pressure, the residue was subjected to silica gel columnchromatography (eluent-ethyl acetate:methanol=9:1), the fractioncontaining the target substance was concentrated, methanol (5 ml) wasadded for crystallization, and the crystals were filtered out andblow-dried to obtain the title compound (157.7 mg, 0.291 mmol, 68.5%) aslight yellow crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.67 (4H, br), 2.47-2.52 (5H, m),2.69 (1H, m), 4.01 (1H, m), 4.20 (1H, dd, J=5.6, 10.8 Hz), 4.30 (1H, dd,J=3.6, 10.8 Hz), 5.02 (1H, d, J=4.4 Hz), 6.51 (1H, d, J=5.2 Hz), 7.11(2H, m), 7.23 (2H, m), 7.46 (2H, m), 7.57-7.61 (3H, m), 8.70-8.75 (3H,m), 8.83 (1H, s).

Example 455N-(4-((6-Cyano-7-(((2R)-3-(diethylamino)-2-hydroxypropyl)oxy)-4-quinolyl)oxy)phenyl)-N′-(4-fluorophenyl)urea

After dissolvingN-(4-(6-cyano-7-((2R)-oxiran-2-yl)methoxy-4-quinolyl)oxyphenyl)-N′-(4-fluorophenyl)urea(200 mg, 0.425 mmol) in tetrahydrofuran (5.0 ml) under a nitrogenatmosphere, diethylamine (1.0 ml) was added and the mixture was stirredovernight at 60° C. The reaction solution was concentrated under reducedpressure, the residue was subjected to silica gel column chromatography(eluent-ethyl acetate:methanol=9:1), the fraction containing the targetsubstance was concentrated, methanol (5 ml) was added forcrystallization, and the crystals were filtered out and blow-dried toobtain the title compound (126.4 mg, 0.233 mmol, 54.7%) as light yellowcrystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.96 (6H, t, J=7.2 Hz), 2.42-2.57(5H, m), 2.64 (1H, m), 3.95 (1H, m), 4.21 (1H, dd, J=5.6, 10.4 Hz), 4.30(1H, dd, J=3.6, 10.4 Hz), 4.91 (1H, d, J=4.4 Hz), 6.51 (1H, d, J=5.2Hz), 7.11 (2H, m), 7.23 (2H, m), 7.46 (2H, m), 7.56-7.60 (3H, m),8.70-8.75 (3H, m), 8.82 (1H, s).

Example 456 N-(4-((6-Cyano-7-(((2R)-2-hydroxy-3-(1-piperidino)propyl)oxy)-4-quinolyl)oxy)phenyl)-N′-(4-fluorophenyl)urea

After dissolvingN-(4-(6-cyano-7-((2R)-oxiran-2-yl)methoxy-4-quinolyl)oxyphenyl)-N′-(4-fluorophenyl)urea(200 mg, 0.425 mmol) in tetrahydrofuran (5.0 ml) under a nitrogenatmosphere, piperidine (0.5 ml) was added and the mixture was stirredovernight at 60° C. The reaction solution was concentrated under reducedpressure, the residue was subjected to silica gel column chromatography(eluent-ethyl acetate:methanol=9:1), the fraction containing the targetsubstance was concentrated, methanol (5 ml) was added forcrystallization, and the crystals were filtered out and blow-dried toobtain the title compound (169.8 mg, 0.306 mmol, 71.9%) as light yellowcrystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.36 (2H, m), 1.47 (4H, m), 2.34-2.51(6H, m), 4.02 (1H, m), 4.20 (1H, dd, J=5.6, 10.4 Hz), 4.30 (1H, dd,J=3.2, 10.4 Hz), 4.93 (1H, d, J=4.4 Hz), 6.51 (1H, d, J=5.2 Hz), 7.11(2H, m), 7.23 (2H, m), 7.46 (2H, m), 7.57-7.62 (3H, m), 8.70-8.75 (3H,m), 8.83 (1H, s).

Example 457 Methyl7-(benzyloxy)-4-(3-chloro-(4-((cyclopropylamino)carbonyl)amino)phenoxy)-6-quinolinecarboxylate

After dissolving methyl4-(4-amino-3-chlorophenoxy)-7-(benzyloxy)-6-quinolinecarboxylate (3.938g, 9.06 mmol) in dimethylformamide (40 ml) under a nitrogen atmosphere,pyridine (1.10 ml, 13.6 mmol) and phenylchloroformate (1.70 ml, 13.6mmol) were added dropwise at room temperature and the mixture wasstirred for 1 hour. Cyclopropylamine (1.88 ml, 27.2 mmol) was addeddropwise, and the mixture was further stirred overnight. The reactionsolution was distributed between ethyl acetate (400 ml) and water (200ml), and then the organic layer was washed with water and concentratedunder reduced pressure, ethyl acetate (40 ml) was added and theprecipitated crystals were filtered out and blow-dried to obtain thetitle compound (2.225 g, 4.30 mmol, 47.4%) as light brown crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.42 (2H, m), 0.65 (2H, m), 2.56 (1H,m), 3.87 (3H, s), 5.39 (2H, s), 6.51 (1H, d, J=5.2 Hz), 7.18 (1H, d,J=2.8 Hz), 7.24 (1H, dd, J=2.8, 9.2 Hz), 7.32 (1H, m), 7.41 (2H, m),7.49 (1H, d, J=2.8 Hz), 7.54 (2H, m), 7.61 (1H, s), 7.97 (1H, s), 8.26(1H, d, J=9.2 Hz), 8.60 (1H, s), 8.67 (1H, d, J=5.2 Hz).

The starting materials were synthesized in the following manner.

Production Example 457-1 Methyl4-(((2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)methyl)amino)-2-hydroxybenzoate

After adding Meldrum acid (7.2 g, 50 mmol), triethyl orthoformate (50ml) and 2-propanol (50 ml) to the publicly known compound methyl4-amino-2-hydroxybenzoate (7.59 g, 45.4 mmol), the mixture was stirredat 100° C. for 1 hour. Upon cooling to room temperature, theprecipitated crystals were filtered out, washed with diethyl ether andblow-dried to obtain the title compound (13.98 g, 43.5 mmol, 95.8%) aswhite crystals.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.76 (6H, s), 3.97 (3H, s), 6.75 (1H,dd, J=2.4, 8.8 Hz), 6.83 (1H, d, J=2.4 Hz), 7.90 (1H, d, J=8.8 Hz), 8.65(1H, m), 11.0 (1H, s), 11.20 (1H, m).

Production Example 457-2 Methyl2-(benzyloxy)-4-(((2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)methyl)amino)benzoate

After suspending methyl4-(((2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)methyl)amino)-2-hydroxybenzoate(13.975 g, 43.5 mmol) in dimethylformamide (140 ml) at room temperatureunder a nitrogen atmosphere, sodium hydride (1.87 g, 46.8 mmol) wasgradually added. After 1.5 hours, benzyl bromide 5.7 ml, 47.9 mmol) wasadded dropwise and the mixture was stirred for 2 days. The reactionsolution was diluted with water (700 ml) and stirred overnight, and theprecipitated crystals were filtered, washed with diethyl ether and driedat 70° C. to obtain the title compound (15.477 g, 37.6 mmol, 86.5%) aswhite crystals.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.76 (6H, s), 3.91 (3H, s), 5.23 (2H,s), 6.83 (1H, s), 6.88 (1H, m), 7.26-7.54 (5H, m), 7.95 (1H, m), 8.62(1H, m), 11.24 (1H, m).

Production Example 457-3 Methyl7-(benzyloxy)-4-oxo-1,4-dihydro-6-quinoline carboxylate

After adding Dowtherm A (160 ml) to methyl2-(benzyloxy)-4-(((2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)methyl)amino)benzoate(15.477 g, 37.6 mmol), the mixture was stirred at 200° C. for 1 hour.Upon cooling to room temperature, the precipitated crystals werefiltered, washed with diethyl ether and blow-dried to obtain the titlecompound (7.19 g, 23.2 mmol, 61.80).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.81 (3H, s), 5.26 (2H, s), 5.97 (1H,d, J=7.6 Hz), 7.09 (1H, s), 7.30-7.53 (5H, m), 7.84 (1H, m), 8.46 (1H,s), 11.69 (1H, m).

Production Example 457-4 Methyl 7-(benzyloxy)-4-chloro-6-quinolinecarboxylate

After adding thionyl chloride (70 ml) and a catalytic amount ofdimethylformamide to methyl7-(benzyloxy)-4-oxo-1,4-dihydro-6-quinolinecarboxylate (7.19 g, 23.2mmol), the mixture was heated to reflux for 3 hours while stirring. Thereaction solution was concentrated under reduced pressure, a 2N sodiumhydroxide solution was gradually added for neutralization, extractionwas performed with ethyl acetate, and the organic layer was washed withwater and saturated brine and dried over anhydrous sodium sulfate. Thesolvent was distilled off, diethyl ether was added for crystallization,and the crystals were filtered out and blow-dried to obtain the titlecompound (4.067 g, 12.4 mmol) as light brown crystals.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 4.00 (3H, s), 5.33 (2H, s), 7.31-7.58(7H, m), 8.66 (1H, s), 8.75 (1H, d, J=5.2 Hz).

Production Example 457-5 Methyl4-(4-amino-3-chlorophenoxy)-7-(benzyloxy)-6-quinolinecarboxylate

After dissolving 4-amino-3-chlorophenol (2.22 g, 15.45 mmol) indimethylsulfoxide (40 ml), sodium hydride (618 mg, 15.45 mmol) wasgradually added at room temperature and the mixture was stirred for 30minutes. Methyl 7-(benzyloxy)-4-chloro-6-quinolinecarboxylate (4.05 g,12.36 mmol) was added, and the mixture was heated at 100° C. for 2 hourswhile stirring. Upon cooling to room temperature, the reaction solutionwas distributed between ethyl acetate and water, and the organic layerwas washed with water and saturated brine and dried over anhydroussodium sulfate. The solvent was distilled off and subjected to silicagel column chromatography (eluent-ethyl acetate), the fractioncontaining the target substance was concentrated, suspended in ethylacetate and diluted with hexane, and the crystals were filtered out andblow-dried to obtain the title compound (3.938 g, 9.06 mmol, 73.3%) aslight brown crystals.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 3.98 (3H, s), 4.11 (2H, m), 5.34 (2H,s), 6.43 (1H, d, J=5.2 Hz), 6.85 (1H, d, J=8.8 Hz), 6.93 (1H, dd, J=2.8,8.8 Hz), 7.14 (1H, d, J=2.8 Hz), 7.30-7.57 (6H, m), 8.62 (1H, d, J=5.2Hz), 8.82 (1H, s).

Example 458N6-(2-Fluoroethyl)-4-(4-((cyclopropylamino)carbonyl)amino-3-methylphenoxy)-7-methoxy-6-quinolinecarboxamide

After dissolving methyl4-(4-amino-3-methylphenoxy)-7-methoxy-6-quinolinecarboxylate (30 mg,0.0736 mmol) in N,N-dimethylformamide (1.4 ml), there were addedtriethylamine (0.071 ml) andbenzotriazol-1-yltris(dimethylamino)phosphonium hexafluorophosphate (63mg) and the mixture was stirred at room temperature for 5 hours. Waterwas added to the reaction solution, extraction was performed with ethylacetate/tetrahydrofuran, the extract was washed with saturated brine anddried over anhydrous magnesium sulfate, and the filtrate was distilledoff under reduced pressure. The obtained crystals were suspended inethanol, and after diluting the suspension with diethyl ether, thecrystals were filtered out, washed with diethyl ether and dried byaspiration to obtain the title compound (22 mg, 0.0486 mmol, 66.03%) aslight yellow crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.41-0.45 (2H, m), 0.63-0.69 (2H, m),2.22 (3H, s), 2.52-2.60 (1H, m), 3.61 (1H, q, J=5.2 Hz), 3.67 (1H, q,J=5.2 Hz), 4.03 (3H, s), 4.52 (1H, t, J=5.2 Hz), 4.64 (1H, t, J=5.2 Hz),6.47 (1H, d, J=5.0 Hz), 6.78 (1H, m), 7.05 (1H, dd, J=2.8 Hz, 8.8 Hz),7.11 (1H, d, J=2.8 Hz), 7.52 (1H, s), 7.63 (1H, s), 7.94 (1H, d, J=8.8Hz), 8.59-8.62 (2H, m), 8.66 (1H, d, J=5.0 Hz).

The starting materials were synthesized in the following manner.

Production Example 458-1 Methyl4-(4-amino-3-methylphenoxy)-7-methoxy-6-quinolinecarboxylate

The title compound (158 mg, 0.4669 mmol, 7.90%) was obtained as browncrystals by the same procedure as in Production Example 395-1 using themethyl 4-chloro-7-methoxy-6-quinolinecarboxylate (1.5 g, 5.9127 mmol)described in WO/0050405 and 4-amino-3-cresol (1.46 g, 11.8254 mmol).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.06 (3H, s), 3.84 (3H, s), 3.95 (3H,s), 4.93 (2H, s), 6.40 (1H, d, J=5.0 Hz), 6.69 (1H, d, J=8.4 Hz), 6.82(1H, d, J=8.4 Hz), 6.86 (1H, s), 7.47 (1H, s), 8.56 (1H, s), 8.62 (1H,d, J=5.0 Hz).

Production Example 458-2 Methyl4-(4-((cyclopropylamino)carbonyl)amino-3-methylphenoxy)-7-methoxy-6-quinolinecarboxylate

4-(4-Amino-3-methylphenoxy)-7-methoxy-6-methoxycarbonylquinoline (158mg, 0.4669 mmol) was used for phenyl carbamating reaction by the sameprocedure as in Production Example 17, and the product was used directlywithout purification for reaction with cyclopropylamine by the sameprocedure as in Example 11 to obtain the title compound (173 mg, 0.4105mmol, 87.92%) as light brown crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.40-0.43 (2H, m), 0.61-0.66 (2H, m),2.20 (3H, s), 2.52-2.57 (1H, m), 3.85 (3H, s), 3.96 (3H, s), 6.45 (1H,d, J=5.4 Hz), 6.75 (1H, s), 7.04 (1H, dd, J=2.4 Hz, 8.8 Hz), 7.10 (1H,d, J=2.4 Hz), 7.51 (1H, s), 7.60 (1H, s), 7.92 (1H, d, J=8.8 Hz), 8.57(1H, s), 8.66 (1H, d, J=5.4 Hz).

Production Example 458-34-(4-((Cyclopropylamino)carbonyl)amino-3-methylphenoxy)-7-methoxy-6-quinolinecarboxylicacid

After dissolvingN-cyclopropyl-N′-[2-methyl-4-(6-methoxycarbonyl-7-methoxy-4-quinolyl)oxyphenyl]urea(173 mg, 0.3972 mmol) in methanol (3 ml), 2N aqueous sodium hydroxide (1ml) was added and the mixture was heated and stirred at 60° C. for 45minutes. The solvent was distilled off under reduced pressure, theprecipitated crystals were redissolved in methanol, and then 1Nhydrochloric acid was added to pH 4 and saturated brine was furtheradded. After extraction with ethyl acetate/tetrahydrofuran, the extractwas washed with saturated brine and dried over anhydrous magnesiumsulfate, the solvent was distilled off under reduced pressure, and theobtained crystals were suspended in acetone/diethyl ether and thenfiltered out and dried by aspiration to obtain the title compound (95mg, 0.2332 mmol, 56.80%) as brown crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.42 (2H, m), 0.66 (2H, m), 2.25 (3H,s), 2.57 (1H, m), 3.51 (1H, brs), 4.05 (3H, s), 6.84 (1H, d, J=6.8 Hz),7.12 (1H, brs), 7.16 (1H, dd, J=2.4 Hz, 8.8 Hz), 7.21 (1H, brs), 7.74(1H, s), 7.92 (1H, s), 8.06 (1H, d, J=8.8 Hz), 8.70 (1H, s), 8.95 (1H,d, J=6.8 Hz).

Example 459N6-(2-Methoxyethyl)-4-(4-((cyclopropylamino)carbonyl)amino-3-methylphenoxy)-7-methoxy-6-quinolinecarboxamide

4-(4-((Cyclopropylamino)carbonyl)amino-3-methylphenoxy)-7-methoxy-6-quinolinecarboxylicacid (30 mg, 0.0736 mmol) and 2-methoxyethylamine (0.0123 ml) were usedfor reaction in the same manner as Example 458, and after purificationby NH silica gel column chromatography (ethyl acetate:methanol=10:1),the obtained crystals were suspended in acetone: diethyl ether=1:5,filtered out, washed with diethyl ether and dried by aspiration toobtain the title compound (17 mg, 0.0366 mmol, 49.73%) as light yellowcrystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.41-0.45 (2H, m), 0.63-0.69 (2H, m),2.22 (3H, s), 2.54-2.60 (1H, s), 3.30 (3H, s), 3.50 (4H, m), 4.04 (3H,s), 6.47 (1H, d, J=5.0 Hz), 6.78 (1H, m), 7.05 (1H, dd, J=2.4 Hz, 8.4Hz), 7.12 (1H, d, J=2.4 Hz), 7.52 (1H, s), 7.63 (1H, s), 7.94 (1H, d,J=8.4 Hz), 8.45 (1H, brs), 8.63 (1H, s), 8.66 (1H, d, J=5.0 Hz).

Example 460N6-Methoxy-4-(4-((cyclopropylamino)carbonyl)amino-3-methylphenoxy)-7-methoxy-6-quinolinecarboxamide

4-(4-((Cyclopropylamino)carbonyl)amino-3-methylphenoxy)-7-methoxy-6-quinolinecarboxylicacid (30 mg, 0.0736 mmol) and methoxylamine hydrochloride (0.0123 ml)were used for reaction in the same manner as Example 458, and afterpurification by NH silica gel column chromatography (ethylacetate:methanol=10:1), the obtained crystals were suspended in ethanol,diluted with hexane, filtered out, washed with hexane and dried byaspiration to obtain the title compound (7 mg, 0.0160 mmol, 21.74%) aslight yellow crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.40-0.45 (2H, m), 0.63-0.68 (2H, m),2.21 (3H, s), 2.51 (3H, s), 2.53-2.59 (1H, m), 3.94 (3H, s), 6.46 (1H,d, J=5.0 Hz), 6.79 (1H, s), 7.04 (1H, d, J=8.4 Hz), 7.09 (1H, s), 7.43(1H, s), 7.63 (1H, s), 7.92 (1H, d, J=8.4 Hz), 8.04 (1H, s), 8.62 (1H,d, J=5.0 Hz), 9.86 (1H, s).

Example 461N-[4-(2-Cyclopropyl-3H-imidazo[4,5-b]pyridin-4-yl)oxyphenyl]-N′-(4-fluorophenyl)urea

A mixture of2-cyclopropyl-7-(4-aminophenyloxy)-3H-imidazo[4,5-b]pyridine (130 mg),p-fluorophenyl isocyanate (0.06 ml), tetrahydrofuran (5 ml) anddimethylformamide (0.5 ml) was stirred at room temperature for 35minutes. NH type silica gel was added to the reaction solution, thesolvent was distilled off under reduced pressure and the reactionproduct was adsorbed onto the silica gel. The silica gel was chargedinto a dry column packed with NH type silica gel, and columnpurification was performed (ethyl acetate, followed by ethylacetate:methanol=10:1). The obtained residue was solidified from ethylacetate-methanol-hexane to obtain 38 mg of the target substance as agray solid.

H-NMR (DMSO-d₆) δ (ppm): 1.02-1.12 (4H, m), 2.04-2.14 (1H, m), 6.34(0.75H, d, J=5.6 Hz), 6.35 (0.25H, d, J=5.6 Hz), 7.05-7.18 (4H, m),7.40-7.55 (4H, m), 7.98 (0.75H, d, J=5.6 Hz), 8.07 (0.25H, d, J=5.6 Hz)8.69 (0.75H, s), 8.70 (0.25H, s), 8.73 (0.75H, s), 8.76 (0.25H, s).

The starting material was obtained in the following manner.

Production Example 461-12-Cyclopropyl-7-(4-aminophenyloxy)-3H-imidazo[4,5-b]pyridine

4-Chloro-2-nitroaminopyridine (9.3 g) was added in small portions at atime to 60 ml of ice-cooled concentrated sulfuric acid. When theaddition was complete, the ice bath was immediately removed and themixture was stirred at room temperature for 2.5 hours. The reactionsolution was developed in ice and concentrated ammonia water was addedto pH 5. The precipitated solid was filtered out and blow-dried at 60°C. to obtain 11.2 g of a yellow solid. The 11.2 g of the solid was addedto a mixture of 10.8 g of p-nitrophenol, 17 ml of Hunig's base and 34 mlof 1-methyl-2-pyrrolidinone, and the mixture was heated and stirred at120° C. for 3 hours. After returning the mixture to room temperature, 50ml of water was added and the precipitated solid was filtered out. Itwas then blow-dried at 60° C. to obtain 4.77 g of a solid. The 4.77 g ofsolid was dissolved in 100 ml of tetrahydrofuran, 2.0 g of palladiumcarbon (Pd—C (10%, wet)) was added and the mixture was refluxed undernormal pressure for 24 hours. After filtering off the Pd—C, the solventwas distilled off under reduced pressure to obtain 5.2 g of areddish-brown oil. The 5.2 g of oil was added to a mixture of 4.6 g ofcyclopropanecarboxylic acid and 50 ml of phosphoric acid, and themixture was heated and stirred at 160° C. for 5 hours. The reactionsolution was developed in ice, neutralized with 5N aqueous sodiumhydroxide and extracted with ethyl acetate. The extract was dried overmagnesium sulfate, and the solvent was distilled off under reducedpressure. The obtained residue was purified by NH type silica gel(chloroform:methanol=10:1). The residue obtained by distilling off thesolvent under reduced pressure was dissolved in a small amount of ethylacetate, the solution was allowed to stand, and the precipitated solidwas filtered out to obtain 130 mg of the target substance as ablackish-violet solid.

¹H-NMR (DMSO-d₆) δ (ppm): 1.00-1.12 (4H, m), 2.05-2.14 (1H, m), 5.08(2H, bs), 6.23 (1H, d, J=5.6 Hz), 6.61 (2H, d, J=8.8 Hz), 6.83 (1.5H, d,J=8.8 Hz), 6.90 (0.5H, d, J=8.8 Hz), 7.92 (0.75H, d, J=5.6 Hz), 8.01(0.25H, d, J=5.6 Hz), 12.75 (0.75H, s), 12.85 (0.25H, s).

Example 462N-[4-(2-Cyclobutanecarbonylaminopyridin-4-yl)oxyphenyl]-N′-(4-fluorophenyl)urea

After adding 70 mg of cyclobutanecarbonyl chloride to a solution of 100mg of N-[4-(2-aminopyridin-4-yl)oxyphenyl]-N′-(4-fluorophenyl)urea, 0.12ml of triethylamine and 10 ml of tetrahydrofuran stirred at roomtemperature, the mixture was further stirred for 15 minutes. NH typesilica gel was added to the reaction solution, the solvent was distilledoff under reduced pressure and the reaction product was adsorbed ontothe silica gel. The silica gel was charged into a dry column packed withNH type silica gel, and column purification was performed(chloroform:methanol=40:1). The obtained residue was solidified fromethyl acetate-methanol-hexane to obtain 64 mg of the target substance asa white solid.

¹H-NMR (DMSO-d₆) δ (ppm): 1.68-1.78 (1H, m), 1.80-1.92 (1H, m),1.95-2.18 (4H, m), 3.24-3.34 (1H, m), 6.63 (1H, dd, J=5.6 Hz, J=2.4 Hz),7.05-7.15 (4H, m), 7.42-7.49 (2H, m), 7.52 (2H, d, J=8.8 Hz), 7.66 (1H,d, J=2.4 Hz), 8.13 (1H, d, J=5.6 Hz), 8.71 (1H, s), 8.77 (1H, s), 10.29(1H, s).

The starting materials were obtained in the following manner.

Production Example 462-1 2-Amino-4-(4-nitrophenoxy)pyridine

A mixture of 15.88 g of 2-amino-4-chloropyridine 34.5 g ofp-nitrophenol, 52 ml of Hunig's base and 100 ml of1-methyl-2-pyrrolidinone was stirred at 160° C. for 15 hours. Water wasadded, extraction was performed with ethyl acetate, and the solvent wasdistilled off under reduced pressure. The residue was purified by columnchromatography (hexane:ethyl acetate=1:1) using NH type silica gel toobtain 3.24 g of the target substance as a light yellow solid.

¹H-NMR (DMSO-d₆) δ (ppm): 6.04 (1H, d, J=2.4 Hz), 6.12 (2H, brs), 6.26(1H, dd, J=6.0 Hz, J=2.4 Hz), 7.32 (2H, d, J=8.8 Hz), 7.92 (1H, d, J=6.0Hz), 8.31 (2H, d, J=8.8 Hz).

Production Example 462-2 2-Amino-4-(4-aminophenoxy)pyridine

After adding 1 g of 2-amino-4-(4-nitrophenoxy)pyridine to a mixture of2.0 g of iron powder, 4.0 g of ammonium chloride, 30 ml of ethanol, 30ml of dimethylformamide and 15 ml of water, the mixture was vigorouslystirred at 100° C. for 10 minutes. The reaction solution was filteredwith celite and the solvent was distilled off under reduced pressure toobtain 0.53 g of the target substance as a solid.

¹H-NMR (DMSO-d6) d (ppm): 5.04 (2H, bs), 5.72 (1H, d, J=1.6 Hz), 5.81(2H, brs), 6.05 (1H, dd, J=5.6 Hz, J=1.6 Hz), 6.57 (2H, d, J=8.8 Hz),6.75 (2H, d, J=8.8 Hz), 7.70 (1H, d, J=5.6 Hz).

Production Example 462-3N-[4-(2-Aminopyridin-4-yl)oxyphenyl]-N′-(4-fluorophenyl)urea

After dissolving 0.53 g of 2-amino-4-(4-aminophenoxy)pyridine in amixture of 20 ml of tetrahydrofuran and 10 ml of dimethylformamide, 0.36ml of p-fluorophenyl isocyanate was added and the mixture was stirredfor 1 hour. NH type silica gel was added to the reaction solution, thesolvent was distilled off under reduced pressure and the reactionproduct was adsorbed onto the silica gel. The silica gel was chargedinto a dry column packed with NH type silica gel, and columnpurification was performed (chloroform:methanol=20:1, followed by 10:1).The solvent was distilled off under reduced pressure to obtain 610 mg ofthe target substance as a white powder.

¹H-NMR (DMSO-d₆) δ (ppm): 5.78 (1H, s), 5.87 (1H, s), 5.89 (1H, s),6.09-6.13 (1H, m), 7.00-7.15 (4H, m), 7.42-7.52 (4H, m), 7.77 (1H, dd,J=6.0 Hz, J=1.6 Hz), 8.69 (1H, s), 8.73 (1H, s).

The following samples were synthesized by the same procedure as inExample 462.

Example 463N-[4-(2-Butanoylaminopyridin-4-yl)oxyphenyl]-N′-(4-fluorophenyl)urea

¹H-NMR (DMSO-d₆) δ (ppm): 0.85 (3H, t, J=7.2 Hz), 1.52 (2H, tq, J=7.2Hz, J=7.2 Hz), 2.30 (2H, t, J=7.2 Hz), 6.63 (1H, dd, J=5.6 Hz, J=2.0Hz), 7.06-7.16 (4H, m), 7.42-7.50 (2H, m), 7.52 (2H, d, J=8.8 Hz), 7.65(1H, d, J=2.0 Hz), 8.14 (1H, d, J=5.6 Hz), 8.72 (1H, s), 8.77 (1H, s),10.45 (1H, s).

Example 464N-{4-[2-(4-Ethoxycarbonylbutanoyl)aminopyridin-4-yl]oxyphenyl}-N′-(4-fluorophenyl)urea

¹H-NMR (DMSO-d₆) δ (ppm): 1.14 (3H, t, J=7.2 Hz), 1.74 (2H, tt, J=7.2Hz, J=7.2 Hz), 2.26 (2H, t, J=7.2 Hz), 2.35 (2H, t, J=7.2 Hz), 4.01 (2H,q, J=7.2 Hz), 6.62 (1H, dd, J=6.0 Hz, J=2.4 Hz), 7.05-7.15 (4H, m),7.41-7.49 (2H, m), 7.51 (2H, d, J=8.8 Hz), 7.62 (1H, d, J=2.4 Hz), 8.14(1H, d, J=6.0 Hz), 8.70 (1H, s), 8.76 (1H, s).

Example 465N-[4-(2-Nicotinoylaminopyridin-4-yl)oxyphenyl]-N′-(4-fluorophenyl)urea

¹H-NMR (DMSO-d₆) δ (ppm): 6.75 (1H, dd, J=5.6 Hz, J=2.4 Hz), 7.06-7.18(4H, m), 7.42-7.58 (5H, m), 7.75 (1H, 2.4 Hz), 8.22 (2H, m), 8.72 (2H,brs), 8.78 (1H, s), 9.06 (1H, s).

Example 466N-{4-[2-(4-Carboxybutanoyl)aminopyridin-4-yl]oxyphenyl}-N′-(4-fluorophenyl)urea

N-{4-[2-(4-Ethoxycarbonylbutyryl)aminopyridin-4-yl]oxyphenyl}-N′-(4-fluorophenyl)urea(22 mg), 2N aqueous sodium hydroxide (1 ml), methanol (2 ml) anddimethylformamide (1 ml) were stirred together at 80° C. for 20 minutes.After returning the mixture to room temperature, 0.4 ml of 5N aqueoushydrochloric acid was added and the precipitated solid was filtered outto obtain 16 mg of the target substance as a white solid.

¹H-NMR (DMSO-d₆) δ (ppm): 1.72 (2H, tt, J=7.2 Hz, J=7.2 Hz), 2.20 (2H,t, J=7.2 Hz), 2.36 (2H, t, J=7.2 Hz), 6.62 (1H, dd, J=6.0 Hz, J=2.0 Hz),7.05-7.15 (4H, m), 7.41-7.49 (2H, m), 7.52 (2H, d, J=8.8 Hz), 7.63 (1H,d, J=2.0 Hz), 8.14 (1H, d, J=6.0 Hz), 8.71 (1H, s), 8.76 (1H, s), 10.46(1H, s), 12.03 (1H, s).

Example 467N-(4-{2-[(Cyclopropylmethyl)aminocarbonyl]pyridin-4-yl}oxyphenyl)-N′-(4-fluorophenyl)urea

After adding 100 mg of4-(4-Aminophenoxy)-2-[(cyclopropylmethyl)aminocarbonyl]pyridine to 5 mlof tetrahydrofuran, 0.075 ml of p-fluorophenyl isocyanate was added atroom temperature and the mixture was stirred for 1 hour. NH type silicagel was added to the reaction solution, the solvent was distilled offunder reduced pressure and the reaction product was adsorbed onto thesilica gel. The silica gel was charged into a dry column packed with NHtype silica gel, and column purification was performed (hexane:ethylacetate=1:1, followed by ethyl acetate and ethyl acetate:methanol=10:1).The solvent was distilled off under reduced pressure, ethyl acetate andhexane were added to the residue, and the precipitated solid wasfiltered out to obtain 25 mg of the target substance as a light yellowpowder.

¹H-NMR (DMSO-d₆) δ (ppm): 0.21 (2H, bs), 0.38 (2H, bs), 1.02 (1H, bs),3.12 (2H, dd, J=6.0 Hz, 6.0 Hz), 7.07-7.21 (5H, m), 7.37 (1H, s),7.43-7.51 (2H, m), 7.56 (2H, d, J=8.0 Hz), 8.49 (1H, d, J=5.2 Hz), 8.74(1H, s), 8.81 (1H, s), 8.83 (1H, t, J=6.0 Hz).

The starting materials were obtained in the following manner.

Production Example 467-14-Chloro-2-[(cyclopropylmethyl)aminocarbonyl]pyridine

4-Chloro-2-carboxypyridine (2.0 g), (aminomethyl)cyclopropanehydrochloride (1.7 g), 1-ethyl-3-(3-diethylaminopropyl)carbodiimidehydrochloride (WSC) (2.9 g), 1-hydroxybenzotriazole (HOBt) (2.3 g),triethylamine (2.1 ml) and tetrahydrofuran (30 ml) were stirred togetherat room temperature for 2 hours. Water was added, extraction wasperformed with ethyl acetate, and then silica gel was added to theextract and the solvent was distilled off under reduced pressure. Thesilica gel was charged into a dry column packed with silica gel andpurified by column chromatography (hexane:ethyl acetate=4:1, followed by2:1) to obtain 1.5 mg of the target substance as a yellow oil.

¹H-NMR (DMSO-d₆) δ (ppm): 0.19-0.30 (2H, m), 0.36-0.43 (2H, m),0.99-1.09 (1H, m), 3.15 (2H, dd, J=6.4 Hz, J=6.4 Hz), 7.75 (1H, d, J=5.6Hz), 8.01 (1H, s), 8.62 (1H, d, J=5.6 Hz), 8.90 (1H, t, J=6.4 Hz).

Production Example 467-22-[(Cyclopropylmethyl)aminocarbonyl]-4-(4-nitrophenoxy)pyridine

4-Chloro-2-[(cyclopropylmethyl)aminocarbonyl]pyridine (1.5 g),p-nitrophenol (2.0 g), Hunig's base (3.1 ml) and1-methyl-2-pyrrolidinone (6.2 ml) were stirred together at 160° C. for 3hours. Water was added, extraction was performed with ethyl acetate, andthe solvent was distilled off under reduced pressure. The residue waspurified by column chromatography (hexane:ethyl acetate=4:1, followed by2:1) using NH type silica gel to obtain 0.35 g of the target substanceas a colorless oil.

¹H-NMR (DMSO-d₆) δ (ppm): 0.19-0.24 (2H, m), 0.36-0.41 (2H, m), 1.02(1H, bs), 3.13 (2H, dd, J=6.4 Hz, J=6.4 Hz), 7.34 (1H, dd, J=5.6 Hz,J=1.6 Hz), 7.44 (2H, d, J=8.8 Hz), 7.55 (1H, d, J=1.6 Hz), 8.33 (2H, d,J=8.8 Hz), 8.61 (1H, d, J=5.6 Hz), 8.90 (1H, t, J=6.4 Hz).

Production Example 467-34-(4-Aminophenoxy)-2-[(cyclopropylmethyl)aminocarbonyl]pyridine

After adding 0.35 g of2-[(cyclopropylmethyl)aminocarbonyl]-4-(4-nitrophenoxy)pyridine to amixture of 0.7 g of iron powder, 1.4 g of ammonium chloride, 10 ml ofethanol, 10 ml of dimethylformamide and 5 ml of water, the mixture wasvigorously stirred at 100° C. for 20 minutes. The reaction solution wasfiltered with celite and the solvent was distilled off under reducedpressure to obtain 0.37 g of the target substance as a light brown oil.

¹H-NMR (DMSO-d₆) δ (ppm): 0.20-0.30 (2H, m), 0.38-0.44 (2H, m),0.99-1.10 (1H, m), 3.13 (2H, dd, J=6.4 Hz, J=6.4 Hz), 5.14-5.19 (2H, m),6.65 (2H, d, J=8.8 Hz), 6.87 (2H, d, J=8.8 Hz), 7.10 (1H, dd, J=5.6 Hz,J=2.8 Hz), 7.35 (1H, d, J=2.8 Hz), 8.47 (1H, d, J=5.6 Hz), 8.81 (1H, t,J=6.4 Hz).

Example 468 N-{4-[2-(Butyroylamino)pyridin-4-yl]oxyphenyl}-N′-cyclopropylurea

Phenyl N-{4-[2-(butyroylamino)pyridin-4-yl]oxyphenyl}carbamate (0.116g), cyclopropylamine (0.034 g), triethylamine (0.041 ml) andtetrahydrofuran (10 ml) were heated together in a sealed tube at 100° C.for 1 hour. NH type silica gel was added to the reaction solution, thesolvent was distilled off under reduced pressure and the reactionproduct was adsorbed onto the silica gel. The silica gel was chargedinto a dry column packed with NH type silica gel, and columnpurification was performed (ethyl acetate). The solvent was distilledoff under reduced pressure, ethyl acetate and hexane were added to theresidue, and the precipitated solid was filtered out to obtain 20 mg ofthe target substance as a white solid.

¹H-NMR (DMSO-d₆) δ (ppm): 0.38-0.45 (2H, m), 0.61-0.67 (2H, m), 0.86(3H, t, J=7.2 Hz), 1.54 (2H, tq, J=7.2 Hz, J=7.2 Hz), 2.31 (2H, t, J=7.2Hz), 2.48-2.58 (1H, m), 6.42 (1H, s), 6.62 (1H, dd, J=5.6 Hz, J=2.0 Hz),7.05 (2H, d, J=8.8 Hz), 7.49 (2H, d, J=8.8 Hz), 7.64 (1H, d, J=2.0 Hz),8.15 (1H, d, J=5.6 Hz), 8.41 (1H, s), 10.82 (1H, s).

The starting materials were obtained in the following manner.

Production Example 468-1 2-Butyroylamino-4-(4-nitrophenoxy)pyridine

Butyroyl chloride (0.93 ml) was added dropwise to a stirred solution of2-amino-4-(4-nitrophenoxy)pyridine (1.0 g), triethylamine (1.8 ml) andtetrahydrofuran (20 ml) at room temperature. After stirring for 1 hour,water was added, extraction was performed with ethyl acetate, theextract was dried over magnesium sulfate and the solvent was distilledoff under reduced pressure. The residue was purified by silica gelchromatography (hexane:ethyl acetate=2:1) to obtain 0.6 g of the targetsubstance as a colorless oil.

¹H-NMR(CDCl₃) δ (ppm): 0.99 (3H, t, J=7.2 Hz), 1.73 (2H, tq, J=7.2 Hz,J=7.2 Hz), 2.36 (2H, t, J=7.2 Hz), 6.72 (1H, dd, J=5.6 Hz, 2.4 Hz), 7.21(2H, d, J=8.8 Hz), 7.95 (1H, d, J=2.4 Hz), 8.22 (1H, d, J=5.6 Hz), 8.25(1H, brs), 8.30 (2H, d, J=8.8 Hz).

Production Example 468-2 4-(4-Aminophenoxy)-2-(butyrylamino)pyridine

A mixture of 0.6 g of 2-butyrylamino-4-(4-nitrophenoxy)pyridine, 1.2 gof iron powder, 2.8 g of ammonium chloride, 10 ml of ethanol, 10 ml ofdimethylformamide and 5 ml of water was vigorously stirred at 100° C.for 10 minutes. The reaction was filtered with celite, the solvent wasdistilled off under reduced pressure, and then water was added to thefiltrate and extraction was performed with ethyl acetate. The extractwas dried over magnesium sulfate and the solvent distilled off underreduced pressure to obtain 0.6 g of the target substance as a lightyellow solid.

¹H-NMR (DMSO-d₆) δ (ppm): 0.86 (3H, t, J=7.2 Hz), 1.54 (2H, tq, J=7.2Hz, J=7.2 Hz), 2.30 (2H, t, J=7.2 Hz), 5.06-5.15 (2H, m), 6.56 (1H, dd,J=5.6 Hz, J=2.4 Hz), 6.61 (2H, d, J=8.8 Hz), 6.81 (2H, d, J=8.8 Hz),7.61 (1H, d, J=2.4 Hz), 8.10 (1H, d, J=5.6 Hz), 10.38 (1H, s).

Production Example 468-3 PhenylN-{4-[2-(butyroylamino)pyridin-4-yl]oxyphenyl}carbamate

Phenyl chloroformate (0.14 ml) was added dropwise to an ice-cooledstirred solution of 4-(4-aminophenoxy)-2-(butyrylamino)pyridine (0.3 g),triethylamine (0.14 ml) and tetrahydrofuran (10 ml). The cooling bathwas removed and the mixture was stirred at room temperature overnight.Silica gel was added to the reaction solution, the solvent was distilledoff under reduced pressure and the reaction product was adsorbed ontothe silica gel. The silica gel was charged into a dry column packed withsilica gel, and column purification was performed (hexane:ethylacetate=2:1, followed by 1:1). The solvent was distilled off underreduced pressure to obtain the target substance as a colorless solid.

¹H-NMR (DMSO-d₆) δ (ppm): 0.86 (3H, t, J=7.2 Hz), 1.54 (2H, tq, J=7.2Hz, J=7.2 Hz), 2.31 (2H, t, J=7.2 Hz), 6.64-6.80 (1H, m), 7.16 (2H, d,J=8.8 Hz), 7.22-7.31 (3H, m), 7.41-7.48 (2H, m), 7.60 (2H, d, J=8.8 Hz),7.66 (1H, d, J=2.0 Hz), 8.17 (1H, dd, J=5.6 Hz, J=2.0 Hz) 10.72 (1H, s),10.90 (1H, s).

Example 4691-[4-(5-Dimethylaminomethyl-6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl]-(3-fluorophenyl)urea

N,N-Dimethylmethyleneammonium iodide (Eschenmoser's salt) (29.5 mg) anddimethylformamide (1.5 ml) were added to1-(3-fluorophenyl)-3-[4-(6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl]urea(50 mg), and the mixture was stirred overnight at 100° C., after whichwater was added and liquid separation and extraction were performed withethyl acetate. The organic layer was concentrated, dried under reducedpressure and subjected to NH silica gel column chromatography (ethylacetate/methanol) to obtain 20 mg of the title compound.

MS Spectrum (ESI): 497 (M+1)

¹H-NMR Spectrum: (DMSOd₆) 2.26 (6H, s), 3.64 (2H, s), 6.73-6.80 (1H, m),6.85 (1H, s), 7.08-7.58 (10H, m), 8.00 (1H, d, J=7.7 Hz), 8.26 (1H, d,J=0.9 Hz), 8.82 (1H, s), 8.92 (1H, s), 12.54 (1H, brs)

Example 4701-{4-[6-(4-Benzyloxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]-2-chlorophenyl}-3-cyclopropylurea

After dissolving 38 mg of1-{4-[6-(4-benzyloxyphenyl)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]-2-chlorophenyl}-3-cyclopropylureain 0.8 ml of tetrahydrofuran, 0.2 ml of tetrabutylammonium fluoride (1 Mtetrahydrofuran solution) was added dropwise and the mixture wasrefluxed for 2 hours. It was then returned to room temperature, waterwas added, and liquid separation and extraction were performed withethyl acetate and tetrahydrofuran. The organic layer was washed withwater and saturated brine, concentrated and dried under reduced pressureto obtain 26 mg of the title compound.

¹H-NMR Spectrum: (DMSOd₆) 0.39-0.44 (2H, m), 0.60-0.70 (2H, m),2.50-2.60 (1H, m), 5.18 (2H, s), 6.93 (1H, s), 7.09-7.50 (10H, m), 7.89(2H, d, J=8.1 Hz), 7.92 (1H, s), 8.13 (1H, d, J=8.1 Hz), 8.28 (1H, d,J=1.0 Hz), 12.60 (1H, brs)

Example 4711-{2-Chloro-4-[6-(4-hydroxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]-phenyl}-3-cyclopropylurea

After adding 2 ml of trifluoroacetic acid and 0.1 ml of thioanisole to24 mg of1-{4-[6-(4-benzyloxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]-2-chlorophenyl}-3-cyclopropylurea,the mixture was stirred at 45° C. for 30 minutes. The reaction mixturewas concentrated under reduced pressure, saturated sodium bicarnobatewater was added to alkalinity, and then liquid separation and extractionwere performed with ethyl acetate and tetrahydrofuran. The organic layerwas washed with saturated brine, dried over anhydrous sodium sulfate,concentrated and dried under reduced pressure to obtain 15 mg of thetitle compound.

¹H-NMR Spectrum: (DMSOd₆) 0.39-0.44 (2H, m), 0.60-0.67 (2H, m),2.52-2.60 (1H, m), 6.80-6.88 (3H, m), 7.12 (1H, d, J=2.0 Hz), 7.27 (1H,dd, J=9.0 Hz, J′=2.0 Hz), 7.40 (1H, d, J=2.0 Hz), 7.76 (2H, d, J=9.0Hz), 7.91 (1H, s), 8.13 (1H, d, J=9.0 Hz), 8.25 (1H, d, J=1.0 Hz), 9.77(1H, brs), 12.50 (1H, brs)

Example 4721-{4-[6-(4-Benzyloxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]phenyl}-3-(3-fluorophenyl)urea

After adding 600 mg of iron powder, 1.1 g of ammonium chloride, 10 ml ofethanol, 20 ml of tetrahydrofuran and ml of water to 550 mg of6-(4-benzyloxyphenyl)-4-(4-nitrophenoxy)-7H-pyrrolo[2,3-d]pyrimidine,the mixture was stirred at 80-85° C. for 1.5 hours. Upon returning themixture to room temperature, it was filtered with celite, and ethylacetate and water were added to the filtrate for liquid separation andextraction. The organic layer was dried over anhydrous sodium sulfate,filtered with plug cotton and concentrated to dryness to obtain 493 mgof an amino compound-containing crude product. After dissolving 490 mgof the crude product in 10 ml of toluene and 10 ml of acetonitrile at90° C., 0.3 ml of 3-fluorophenyl isocyanate was added and the mixturewas stirred for 1 hour. After cooling to room temperature, theprecipitated crystals were filtered out and dried to obtain 450 mg ofthe title compound.

¹H-NMR Spectrum: (DMSOd₆) 5.17 (2H, s), 6.77 (1H, dt, J=2.9, 7.8 Hz),6.88 (1H, d, J=1.2 Hz), 7.08-7.53 (14H, m), 7.88 (2H, d, J=9.1 Hz), 8.25(1H, s), 8.75 (1H, s), 8.98 (1H, s), 12.56 (1H, brs)

Example 4731-(3-Fluorophenyl)-3-{4-[6-(4-hydroxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]phenyl}urea

After dissolving 377 mg of1-{4-[6-(4-benzyloxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]phenyl}-3-(3-fluorophenyl)ureain 4 ml of trifluoroacetic acid and 0.4 ml of thioanisole, the solutionwas stirred at 45° C. for 40 minutes. It was then returned to roomtemperature, potassium carbonate was added to alkalinity, and liquidseparation and extraction were performed with an ethylacetate-tetrahydrofuran (5:1) mixed solvent. The organic layer wasconcentrated to dryness to obtain 310 mg of the title compound.

¹H-NMR Spectrum: (DMSOd₆) 6.70-6.80 (2H, m), 6.82 (2H, d, J=8.3 Hz),7.10-7.52 (7H, m), 7.75 (2H, d, J=8.3 Hz), 8.23 (1H, s), 8.85 (1H, s),8.98 (1H, s), 8.98 (1H, s), 12.48 (1H, brs)

Example 474 1-(4-{6-[4-(2-Diethylaminoethoxy)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy}phenyl)-3-(3-fluorophenyl) urea

After dissolving 114 mg of1-(3-fluorophenyl)-3-{4-[6-(4-hydroxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]phenyl}urea in 2 ml of dimethylformamide, therewere added 44 mg (ca. 1 equivalent) of 2-chloroethyldiethylaminehydrochloride and 63 mg (2.5 equivalents) of potassium bicarbonate, andthe mixture was stirred at 50-60° C. for 16 hours. There were then added17 mg of 2-chloroethyldiethylamine hydrochloride, 20 mg of potassiumbicarbonate and 1 ml of dimethylformamide, and the mixture was stirredovernight at the same temperature. It was then returned to roomtemperature, water was added, and liquid separation and extraction wereperformed with ethyl acetate-tetrahydrofuran. The organic layer waswashed with water and saturated brine, concentrated and subjected to NHsilica gel column chromatography (hexane-ethyl acetate) to obtain 33 mgof a crude solid containing the title compound. This was washed withethyl acetate to obtain 5 mg of the title compound.

MS Spectrum (ESI): 555 (M+1),

¹H-NMR Spectrum: (DMSOd₆) 0.96 (6H, t, J=7.4 Hz) 2.53 (4H, q, J=7.4 Hz),2.78 (2H, t, J=6.2 Hz), 4.06 (2H, t, J=6.2 Hz), 6.74-6.88 (2H, m), 7.02(2H, d, J=9.0 Hz), 7.09-7.54 (7H, m), 7.86 (2H, d, J=9.0 Hz), 8.25 (1H,s), 8.83 (1H, brs), 8.96 (1H, brs), 12.50 (1H, brs)

The intermediate was synthesized in the following manner.

Production Example 474-16-(4-Benzyloxyphenyl)-4-(4-nitrophenoxy)-7H-pyrrolo[2,3-d]pyrimidine

After adding 2.97 of potassium carbonate and 30 ml of dimethylformamideto 3.09 g of 4-nitrophenol and stirring the mixture at 130° C. for 10minutes, 2.49 g of6-(4-benzyloxyphenyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidine was added andthe mixture was further stirred at 130° C. for 5 hours and at 135° C.overnight. After returning the mixture to room temperature, water wasadded, the precipitated solid was filtered out and subjected to NHsilica gel column chromatography (ethyl acetate) and silica gel columnchromatography (ethyl acetate), and then ether and ethyl acetate wereadded prior to sonication. The solid was filtered out to obtain 1.2 g ofthe title compound.

¹H-NMR Spectrum: (DMSOd₆) 5.18 (2H, s), 6.99 (1H, d, J=1.7 Hz),7.08-7.13 (2H, m), 7.28-7.48 (5H, m), 7.53-7.60 (2H, m), 7.88-7.93 (2H,m), 8.30-8.35 (3H, m), 12.71 (1H, brs)

Example 4751-(3-Fluorophenyl)-3-{4-[6-(4-pyrrolidin-1-ylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]phenyl}urea

After adding 646 mg of 4-nitrophenol, 817 mg of potassium carbonate and6.3 ml of dimethylformamide to 630 mg of4-chloro-6-(4-pyrrolidin-1-ylphenyl)-7H-pyrrolo[2,3-d]pyrimidine, themixture was stirred overnight at 130° C. Water was added, liquidseparation and extraction were performed with ethyl acetate, and theorganic layer was washed with water and saturated brine and concentratedto dryness to obtain 510 mg of a solid. After adding to the solid 500 mgof iron powder, 1 g of ammonium chloride, 20 ml of ethanol, 10 ml oftetrahydrofuran 10 ml and 3 ml of water, the mixture was stirred at 80°C. for 2 hours. Upon returning the mixture to room temperature, it wasfiltered with celite, and ethyl acetate, tetrahydrofuran and water wereadded to the filtrate for liquid separation and extraction, after whichthe organic layer was dried over anhydrous sodium sulfate, filtered withplug cotton and concentrated to dryness to obtain 380 mg of a crudeproduct. After adding thereto 5 ml of toluene, 5 ml of acetonitrile and5 ml of tetrahydrofuran for dissolution at 100° C., the solution wasstirred for 1 hour. It was then allowed to cool to room temperature andthe precipitated crystals were filtered out, washed with ether and driedunder reduced pressure to obtain 40 mg of the title compound.

MS Spectrum (ESI; nega): 509 (M+1)

¹H-NMR Spectrum: (DMSOd₆) 1.85-2.02 (4H, m), 3.10-3.32 (4H, m), 6.42(1H, d, J=8.2 Hz), 6.60 (1H, d, J=8.2 Hz), 6.70-6.80 (2H, m), 7.02-7.53(9H, m), 8.00 (1H, s), 8.99 (1H, s), 9.17 (1H, s), 11.81 (1H, brs)

The intermediates were synthesized in the following manner.

Production Example 475-12-Amino-5-(4-pyrrolidine-1-phenyl)-1H-pyrrole-3-carboxylic acid ethylester

After adding 150 ml of ethanol to 13.8 g of 2-amidino-ethyl acetateester hydrochloride (publicly known compound described in Liebigs Ann.Chem., 1895(1977)), there was further added 5.94 g of sodium ethoxide(0.97 equivalent with respect to the 2-amidino-ethyl acetate esterhydrochloride) at 0° C. and the mixture was stirred for 10 minutes undera nitrogen atmosphere. There was further added 12 g of2-bromo-1-(4-pyrrolidine-1-phenyl)ethanone (Lancaster), and the mixturewas stirred at room temperature for 48 hours. Ethyl acetate was addedprior to sonication, the solid was filtered out, and the filtrate wasconcentrated and subjected to silica gel column chromatography (ethylacetate) to obtain 4.82 g of the title compound.

¹H-NMR Spectrum: (DMSOd₆) 1.22 (3H, d, J=7.3 Hz), 1.88-1.98 (4H, m),3.16-3.24 (4H, m), 4.06-4.14 (2H, m), 5.52 (2H, s), 6.13 (1H, d, J=2.8Hz), 6.48 (2H, d, J=8.8 Hz), 7.28 (2H, d, J=8.8 Hz), 10.48 (1H, s)

Production Example 475-26-(4-Pyrrolidin-1-ylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-01

After adding 8 ml of formic acid, 31.8 ml of formamide and 15.9 ml ofdimethylformamide to 4.80 g of2-amino-5-(4-pyrrolidine-1-phenyl)-1H-pyrrole-3-carboxylic acid ethylester and stirring the mixture at 140° C. for 48 hours, it was allowedto stand at room temperature for 24 hours. The precipitated solid wasfiltered out and dried under reduced pressure to obtain 3.0 g of thetitle compound.

¹H-NMR Spectrum: (DMSOd₆) 1.86-2.00 (4H, m), 3.08-3.13 (4H, m), 6.54(2H, d, J=8.8 Hz), 6.62 (1H, s), 7.61 (2H, d, J=8.8 Hz), 7.78 (1H, s),12.40 (1H, brs)

Production Example 475-34-Chloro-6-(4-pyrrolidin-1-ylphenyl)-7H-pyrrolo[2,3-d]pyrimidine

After adding 20 ml of phosphorous oxychloride to 1.9 g of6-(4-pyrrolidin-1-ylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ol and stirringthe mixture at 140° C. for 3 hours, the reaction system was returned toroom temperature and concentrated. Ice water was added to the residue,sodium bicarbonate was used for neutralization, and liquid separationand extraction were performed with ethyl acetate. The organic layer wasdried over sodium sulfate and concentrated to dryness to obtain 12 g ofa crude product containing the title compound.

¹H-NMR Spectrum: (DMSOd₆) 1.86-2.02 (4H, m), 3.10-3.32 (4H, m), 6.60(2H, d, J=8.9 Hz), 6.77 (1H, d, J=2.0 Hz), 7.81 (2H, d, J=8.9 Hz), 8.46(1H, s), 12.70 (1H, brs)

Example 476N-{4-[6-(Methylamino)carbonyl-7-methoxy-4-quinolyl]oxyphenyl}-N′-(4-fluorophenyl)urea

The title compound (85 mg) was obtained as light yellow crystals from4-(4-amino-phenoxy)-7-methoxy-quinoline-6-carboxylic acidmethylamide (65mg) and 4-fluorophenyl isocyanate (0.05 ml), by the same procedure as inExample 10.

¹H-NMR (DMSO-d₆) δ (ppm) 2.81-2.84 (3H, m), 4.00 (3H, s), 6.46 (1H, s),7.07-7.24 (4H, m), 7.43-7.61 (5H, m), 8.32-8.38 (1H, m), 8.59-8.65 (2H,m), 8.80 (1H, brs), 8.89 (1H, brs)

The starting materials were synthesized by the following 3 steps.

Production Example 476-1 4-Chloro-7-methoxyquinoline-6-carboxylic acidmethylamide

After dissolving 7-methoxy-4-chloro-quinoline-6-carbonyl chloridesynthesized by the method of Production Example 152-2 from7-methoxy-4-oxo-1,4-dihydroquinoline-6-carboxylic acid (947 mg) intetrahydrofuran (70 ml), the solution was cooled to 0° C. A 40% aqueousmethylamine solution (0.4 ml) was added, and the mixture was stirred atroom temperature for 30 minutes. Water was added, extraction wasperformed 3 times with ethyl acetate, and the organic layers werecombined, washed with water and saturated brine, dried over sodiumsulfate and then dried under reduced pressure to obtain the titlecompound (710 mg).

¹H-NMR (DMSO-d₆) δ (ppm) 3.07-3.10 (3H, m), 4.12 (3H, s), 7.40-7.43 (1H,m), 7.56 (1H, s), 7.83 (1H, brs), 8.73-8.77 (1H, m), 9.13 (1H, s)

Production Example 476-27-Methoxy-4-(4-nitrophenoxy)quinoline-6-carboxylic acid methylamide

The title compound (736 mg) was obtained as light yellow crystals from4-chloro-7-methoxyquinoline-6-carboxylic acid methylamide (492 mg) and4-nitrophenol (492 mg), by the same procedure as in Production Example7.

¹H-NMR (DMSO-d₆) δ (ppm) 2.76-2.82 (3H, m), 4.02 (3H, s), 6.86 (1H, d,J=5.2 Hz), 7.45-7.51 (2H, m), 7.56 (1H, s), 8.32-8.38 (2H, m), 8.45 (1H,s), 8.76-8.79 (1H, m)

Production Example 476-34-(4-Aminophenoxy)-7-methoxyquinoline-6-carboxylic acid methylamide

The title compound (250 mg) was obtained from7-methoxy-4-(4-nitrophenoxy)-quinoline-6-carboxylic acid methylamide(736 mg), by the same procedure as in Production Example 10.

¹H-NMR (DMSO-d₆) δ (ppm) 2.81-2.84 (3H, m), 3.99 (3H, s), 5.14-5.19 (2H,m), 6.39 (1H, d, J=5.2 Hz), 6.45 (2H, d, J=8.4 Hz), 6.92 (2H, d, J=8.4Hz), 7.46 (1H, s), 8.30-8.38 (1H, m), 8.57-8.61 (2H, m)

Example 477N-{4-[6-(Methylamino)carbonyl-7-methoxy-4-quinolyl]oxyphenyl}-N′-(2-thiazolyl)urea

The title compound (32 mg) was obtained as light yellow crystals from4-(4-amino-phenoxy)-7-methoxyquinoline-6-carboxylic acid methylamide (65mg) and phenyl N-(2-thiazolyl)carbamate (49 mg), by the method describedin Example 11.

¹H-NMR (DMSO-d₆) δ (ppm) 2.80-2.85 (3H, m), 4.00 (3H, s), 6.47 (1H, d,J=5.2 Hz), 7.05-7.15 (1H, m), 7.25 (2H, d, J=8.8 Hz), 7.35-7.40 (1H, m),7.50 (1H, s), 7.62 (2H, d, J=8.8 Hz), 8.58-8.66 (2H, m)

Example 478N-{4-[6-(Dimethylamino)carbonyl-7-methoxy-4-quinolyl]oxyphenyl}-N′-(2-thiazolyl)urea

The title compound (60 mg) was obtained as light yellow crystals from4-(4-aminophenoxy)-7-methoxyquinoline-6-carboxylic acid dimethylamide(100 mg) and phenyl N-(2-thiazolyl) carbamate (60 mg), by the methoddescribed in Example 11.

¹H-NMR (DMSO-d₆) δ (ppm) 2.78 (3H, s), 3.00 (3H, s), 3.97 (3H, s), 6.47(1H, d, J=5.2 Hz), 7.05-7.15 (1H, m), 7.24 (2H, d, J=8.8 Hz), 7.35-7.39(1H, m), 7.48 (1H, s), 7.60 (2H, d, J=8.8 Hz), 8.04 (1H, s), 8.62 (1H,d, J=5.2 Hz)

The starting materials were synthesized by the following 3 steps.

Production Example 478-1 4-Chloro-7-methoxy-quinoline-6-carboxylic aciddimethylamide

After dissolving 7-methoxy-4-chloro-quinoline-6-carbonyl chloridesynthesized by the method of Production Example 152-2 from7-methoxy-4-oxo-1,4-dihydroquinoline-6-carboxylic acid (1.0 g) intetrahydrofuran (60 ml), the solution was cooled to 0° C.Diisopropylethylamine (1.6 ml) and a 2.0 M dimethylamine tetrahydrofuransolution (3 ml) were added and the mixture was stirred overnight at roomtemperature. Water was added, extraction was performed 3 times withethyl acetate, and the organic layers were combined, washed with waterand saturated brine, dried over sodium sulfate and then dried underreduced pressure to obtain the title compound (933 mg).

¹H-NMR (DMSO-d₆) δ (ppm) 2.75 (3H, s), 3.01 (3H, s), 3.97 (3H, s), 7.57(1H, s), 7.63 (1H, d, J=4.8 Hz), 7.93 (1H, s), 8.78 (1H, d, J=4.8 Hz)

Production Example 478-27-Methoxy-4-(4-nitrophenoxy)-quinoline-6-carboxylic acid dimethylamide

The title compound (904 mg) was obtained as light yellow crystals fromacid dimethylamide (933 mg) and 4-nitrophenol (737 mg), by the sameprocedure as in Production Example 10.

¹H-NMR (DMSO-d₆) δ (ppm) 2.75 (3H, s), 2.99 (3H, s), 3.95 (3H, s), 6.87(1H, d, J=5.2 Hz), 7.46 (2H, d, J=7.2 Hz), 7.55 (1H, s), 7.94 (1H, s),8.33 (2H, d, J=7.2 Hz), 8.76 (1H, d, J=5.2 Hz)

Production Example 478-34-(4-Aminophenoxy)-7-methoxyquinoline-6-carboxylic acid dimethylamide

The title compound (511 mg) was obtained from7-methoxy-4-(4-nitrophenoxy)quinoline-6-carboxylic acid dimethylamide(904 mg), by the same procedure as in Production Example 10.

¹H-NMR(CDCl₃) δ (ppm) 2.90 (3H, s), 3.18 (3H, s), 3.98 (3H, s), 6.43(1H, d, J=5.6 Hz), 6.75 (2H, d, J=8.8 Hz), 6.95 (2H, d, J=8.8 Hz), 7.45(1H, s), 8.27 (1H, s), 8.57 (1H, d, J=5.6 Hz)

Example 479N-{4-[6-(Cyclopropylamino)carbonyl-7-methoxy-4-quinolyl]oxyphenyl}-N′-(4-fluorophenyl)urea

After dissolving theN-[4-(6-carboxy-7-methoxy-4-quinolyl)oxyphenyl]-N′-(4-fluorophenyl)urea(60 mg) synthesized in Example 341 in dimethylformamide (1.5 ml), therewere added 1-ethyl-3-(3-diethylaminopropyl)-carbodiimide hydrochloride(39 mg), 1-hydroxy-1H-benzotriazole monohydrate (31 mg), triethylamine(30 μl) and cyclopropylamine (0.05 ml) and the mixture was stirredovernight at room temperature. The reaction solution was distributedbetween ethyl acetate and water, and the organic layer was washed withwater and then dried over anhydrous sodium sulfate. After distilling offthe solvent, crystals were precipitated with ethyl acetate, filtered outand dried under reduced pressure to obtain the title compound (29 mg) aswhite crystals.

¹H-NMR(CDCl₃) δ (ppm) 0.45-0.59 (2H, m), 0.67-0.73 (2H, m), 2.82-2.89(1H, m), 3.97 (3H, s), 6.45 (1H, d, J=5.2 Hz), 7.08-7.23 (4H, m),7.43-7.50 (3H, m), 7.55-7.60 (2H, m), 8.32-8.35 (1H, m), 8.42 (1H, s),8.62 (1H, d, J=5.2 Hz), 8.75 (1H, brs), 8.84 (1H, brs)

Example 480N-[4-(6-Aminomethyl-7-methoxyguinolin-4-yloxy)-phenyl]-N′-phenylureatrifluoroacetate

After dissolving theN-[4-(6-cyano-7-methoxyguinolin-4-yloxy)phenyl]-N′-phenylurea (100 mg)synthesized in Example 37 in an ethanol (5 ml) and tetrahydrofuran (5ml) mixed solvent, there were added trifluoroacetic acid (0.5 ml) and50% palladium-carbon (50 mg), and the mixture was stirred overnightunder a hydrogen atmosphere. After filtering off the palladium carbon,the filtrate was concentrated. The obtained residue was washed withtetrahydrofuran to obtain the title compound (70 mg).

¹H-NMR (DMSO-d₆) δ (ppm) 4.02 (3H, s), 4.24 (2H, s), 6.64 (1H, d, J=5.6Hz), 6.94-6.99 (1H, m), 7.21-7.31 (4H, m), 7.44-7.49 (2H, m), 7.53 (1H,s), 7.62-7.66 (2H, m), 8.25 (2H, brs), 8.48 (1H, s), 8.76 (1H, d, J=5.6Hz), 8.87 (1H, brs), 9.04 (1H, brs)

Example 481N-[4-(6-Acetylaminomethyl-7-methoxyguinolin-4-yloxy)phenyl]-N′-phenylurea

After dissolvingN-[4-(6-aminomethyl-7-methoxy-quinolin-4-yloxy)phenyl]-N′-phenylureatrifluoroacetate (40 mg) in pyridine (1.0 ml) and acetic anhydride (1.0ml), the solution was stirred overnight at room temperature. Thereaction solution was concentrated under reduced pressure and theobtained crude product was crystallized with ethyl acetate to obtain thetitle compound (13 mg).

¹H-NMR (DMSO-d₆) δ (ppm) 1.90 (3H, s), 3.98 (3H, s), 4.37-4.40 (2H, m),6.46 (1H, d, J=5.2 Hz), 6.93-6.99 (1H, m), 7.18-7.30 (4H, m), 7.40 (1H,s), 7.45 (2H, d, J=7.6 Hz), 7.59 (2H, d, J=8.8 Hz), 8.06 (1H, s),8.38-8.44 (1H, m), 8.59 (1H, d, J=5.2 Hz) 8.70 (1H, s), 8.83 (1H, s)

Example 482N-(2-Fluoro-4-[(6-carbamoyl-7-methoxy-4-quinolyl)oxy]phenyl)-N′-cyclopropylurea

Cyclopropylamine (0.10 ml) was added to dimethylsulfoxide (0.8 ml), andthen [4-(6-carbamoyl-7-methoxyquinolin-4-yloxy)-2-fluorophenyl]carbamicacid phenyl ester (80 mg) was dissolved therein and the mixture wasstirred for 10 minutes. Water and ethyl acetate were added to thereaction solution and the precipitated crystals were filtered out toobtain the title compound (33 mg).

¹H-NMR (DMSO-d₆) δ (ppm) 0.38-0.41 (2H, m), 0.62-0.66 (2H, m), 2.51-2.59(1H, m), 4.01 (3H, s), 6.52 (1H, d, J=5.2 Hz), 6.78-6.81 (1H, m),7.04-7.09 (1H, m), 7.28-7.34 (1H, m), 7.50 (1H, s), 7.72 (1H, brs), 7.84(1H, brs), 8.16-8.23 (2H, m), 8.63-8.67 (2H, m)

The starting material was synthesized in the following manner.

Production Example 482-1[4-(6-Carbamoyl-7-methoxyquinolin-4-yloxy)-2-fluorophenyl]carbamic acidphenyl ester

The title compound was obtained from the6-carbamoyl-4-(4-amino-3-fluorophenoxy)-7-methoxyquinoline synthesizedin Production Example 152-5, by the method described in ProductionExample 17.

H-NMR(CDCl₃) δ (ppm) 4.13 (3H, s), 5.90 (1H, brs), 6.53 (1H, d, J=5.6Hz), 6.99-7.06 (2H, m), 7.20-7.30 (4H, m), 7.40-7.45 (2H, m), 7.59 (1H,s), 7.80 (1H, brs), 8.24 (1H, brs), 8.68 (1H, d, J=5.6 Hz), 9.27 (1H, s)

Example 483N-(2-Fluoro-4-[(6-carbamoyl-7-methoxy-4-quinolyl)oxy]phenyl)-N′-(2-thiazolyl)urea

The title compound (24 mg) was obtained as light yellow crystals fromthe 6-carbamoyl-4-(4-amino-3-fluorophenoxy)-7-methoxyquinoline (60 mg)and phenyl N-(2-thiazolyl)carbamate (60 mg) synthesized in Example152-5, by the method described in Example 224.

¹H-NMR (DMSO-d₆) δ (ppm) 4.02 (3H, s), 6.57 (1H, d, J=5.2 Hz), 7.12-7.18(2H, m), 7.37-7.45 (2H, m), 7.51 (1H, s), 7.73 (1H, brs), 7.85 (1H,brs), 8.18-8.26 (1H, m), 8.64-8.69 (2H, m)

Example 484N-{4-[6-(Methylamino)carbonyl-7-methoxy-4-quinolyl]oxyphenyl}-N′-cyclopropylurea

The title compound (33 mg) was obtained as light yellow crystals fromN-[4-(7-methoxy-6-methylcarbamoylquinolin-4-yloxy)phenyl]carbamic acidphenyl ester (80 mg) and cyclopropylamine (20 mg), by the methoddescribed in Example 11.

¹H-NMR (DMSO-d₆) δ (ppm) 0.39-0.43 (2H, m), 0.62-0.68 (2H, m), 2.50-2.58(1H, m), 2.84 (3H, d, J=4.8 Hz), 4.02 (3H, s), 6.43-6.46 (2H, m),7.14-7.20 (2H, m), 7.50 (1H, s), 7.53-7.57 (2H, m), 8.35-8.38 (1H, m),8.47 (1H, brs), 8.61 (1H, s), 8.64 (1H, d, J=5.2 Hz)

The starting material was synthesized in the following manner.

Production Example 484-1N-[4-(7-Methoxy-6-methylcarbamoylquinolin-4-yloxy)phenyl]carbamic acidphenyl ester

The title compound (60 mg) was obtained from4-(4-aminophenoxy)-7-methoxyquinoline-6-carboxylic acid methylamide (53mg), by the method described in Production Example 17.

¹H-NMR(CDCl₃) δ (ppm) 3.08 (3H, d, J=4.8 Hz), 4.12 (3H, s), 6.48 (1H, d,J=5.2 Hz), 7.14-7.29 (6H, m), 7.37-7.45 (2H, m), 7.55-7.63 (3H, m), 7.89(1H, brs), 8.63 (1H, d, J=5.2 Hz), 9.28 (1H, s)

Example 485N-(2-Fluoro-4-[(6-carbamoyl-7-methoxy-4-quinolyl)oxy]phenyl)-N′-cyclobutylurea

The title compound (28 mg) was obtained from[4-(6-carbamoyl-7-methoxyquinolin-4-yloxy)-2-fluorophenyl]carbamic acidphenyl ester (73 mg) and cyclobutylamine (28 mg), by the methoddescribed in Example 11.

¹H-NMR (DMSO-d₆) δ (ppm) 2.52-2.67 (2H, m), 2.72-2.87 (2H, m), 2.14-2.26(2H, m), 4.01 (3H, s), 4.04-4.18 (1H, m), 6.51 (1H, d, J=5.2 Hz), 6.88(1H, d, J=8.0 Hz), 7.02-7.08 (1H, m), 7.27-7.34 (1H, m), 7.50 (1H, s),7.72 (1H, brs), 7.84 (1H, brs), 8.15-8.26 (2H, m), 8.63-8.67 (2H, m)

Example 486N-(2-Fluoro-4-[(6-carbamoyl-7-methoxy-4-quinolyl)oxy]phenyl)-N′-cyclopentylurea

The title compound (68 mg) was obtained from[4-(6-carbamoyl-7-methoxyquinolin-4-yloxy)-2-fluorophenyl]carbamic acidphenyl ester (80 mg) and cyclopentylamine (38 mg), by the methoddescribed in Example 11.

¹H-NMR (DMSO-d₆) δ (ppm) 1.30-1.40 (2H, m), 1.49-1.59 (4H, m), 1.78-1.88(2H, m), 3.88-3.98 (1H, m), 4.01 (3H, s), 6.51 (1H, d, J=5.2 Hz), 6.67(1H, d, J=7.2 Hz), 7.02-7.07 (1H, m), 7.27-7.33 (1H, m), 7.50 (1H, s),7.72 (1H, brs), 7.84 (1H, brs), 8.20-8.28 (2H, m), 8.63-8.67 (2H, m)

Example 487N-(2-Fluoro-4-[(6-carbamoyl-7-methoxy-4-quinolyl)oxy]phenyl)-N′-(2-propyl)urea

The title compound (39 mg) was obtained from[4-(6-carbamoyl-7-methoxyquinolin-4-yloxy)-2-fluorophenyl]carbamic acidphenyl ester (60 mg) and isopropylamine (25 mg), by the method describedin Example 11.

¹H-NMR (DMSO-d₆) δ (ppm) 1.09 (6H, d, J=6.4 Hz), 3.70-3.80 (1H, m), 4.01(3H, s), 6.50-6.55 (2H, m), 7.03-7.07 (1H, m), 7.27-7.34 (1H, m), 7.50(1H, s), 7.72 (1H, brs), 7.84 (1H, brs), 8.20-8.27 (2H, m), 8.63-8.66(2H, m)

Example 488N-[4-(6-Carbamoyl-7-methoxy-4-quinolyl)oxy-2-methyl-phenyl]-N′-cyclopropylurea

Cyclopropylamine (0.10 ml) was added to dimethylsulfoxide (0.8 ml), andthen [4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy)-2-methylphenyl]carbamicacid phenyl ester (136 mg) was dissolved therein and the mixture wasstirred for 10 minutes. Water and ethyl acetate were added to thereaction solution and the precipitated crystals were filtered out toobtain the title compound (90 mg).

¹H-NMR (DMSO-d₆) δ (ppm) 0.38-0.44 (2H, m), 0.62-0.69 (2H, m), 2.22 (3H,s), 2.53-2.60 (1H, m), 4.03 (3H, s), 6.46 (1H, d, J=5.2 Hz), 6.75-6.79(1H, m), 7.01-7.12 (2H, m), 7.50 (1H, s), 7.62 (1H, s), 7.73 (1H, brs),7.85 (1H, brs), 7.90-7.96 (1H, m), 8.62-8.69 (2H, m)

The starting materials were synthesized by the following 3 steps.

Production Example 488-16-Carbamoyl-4-(3-methyl-4-nitrophenoxy)-7-methoxyquinoline

The title compound (1.2 g) was obtained from7-methoxy-4-chloroquinoline-6-carboxyamide (1.0 g) and4-nitro-3-methylphenol (810 mg), in the same manner as ProductionExample 7.

¹H-NMR (DMSO-d₆) δ (ppm) 2.54 (3H, s), 4.00 (3H, s), 6.80 (1H, d, J=5.2Hz), 7.28-7.32 (1H, m), 7.41-7.43 (1H, m), 7.54 (1H, s), 7.72 (1H, brs),7.83 (1H, brs), 8.13-8.16 (1H, m), 8.55 (1H, s), 8.72-8.76 (1H, m)

Production Example 488-24-(6-Carbamoyl-7-methoxy-4-quinolyl)oxy-2-methyl-phenylamine

The title compound (0.22 g) was obtained from6-carbamoyl-4-(3-methyl-4-nitrophenoxy)-7-methoxyquinoline (1.2 g), inthe same manner as Production Example 8.

¹H-NMR (DMSO-d₆) δ (ppm) 2.07 (3H, s), 4.00 (3H, s), 4.88-4.94 (2H, m),6.39 (1H, d, J=5.2 Hz), 6.70-6.71 (1H, m), 6.77-6.88 (2H, m), 7.46 (1H,s), 7.70 (1H, brs), 7.83 (1H, brs), 8.59 (1H, d, J=5.2 Hz), 8.66 (1H, s)

Production Example 488-3[4-(6-Carbamoyl-7-methoxy-4-quinolyl)oxy-2-methylphenyl]carbamic acidphenyl ester

The title compound was obtained from4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2-methylphenylamine, by themethod described in Production Example 141-1.

¹H-NMR(CDCl₃) δ (ppm) 2.38 (3H, s), 4.12 (3H, s), 5.88 (1H, brs), 6.49(1H, d, J=5.6 Hz), 6.76 (1H, brs), 7.04-7.09 (2H, m), 7.20-7.29 (3H, m),7.38-7.45 (2H, m), 7.54 (1H, s), 7.80 (1H, brs), 7.94 (1H, brs), 8.64(1H, d, J=5.6 Hz), 9.29 (1H, s)

Example 489 N-[4-(6-Carbamoyl-7-methoxy-4-quinolyl)oxy)-2-trifluoromethyl-phenyl]-N′-cyclopropylurea

Cyclopropylamine (0.10 ml) was added to dimethylsulfoxide (0.8 ml), andthen[4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy)-2-trifluoromethylphenyl]carbamicacid phenyl ester (140 mg) was dissolved therein and the mixture wasstirred for 10 minutes. Water and ethyl acetate were added to thereaction solution and the precipitated crystals were filtered out toobtain the title compound (103 mg).

¹H-NMR (DMSO-d₆) δ (ppm) 0.38-0.44 (2H, m), 0.62-0.68 (2H, m), 2.51-2.59(1H, m), 4.02 (3H, s), 6.52 (1H, d, J=5.2 Hz), 7.18-7.24 (1H, m),7.50-7.62 (3H, m), 7.70-7.77 (2H, m), 7.84 (1H, brs), 8.07-8.14 (1H, m),8.64-8.69 (2H, m)

The starting material was synthesized by the following 3 steps.

Production Example 489-16-Carbamoyl-4-(3-trifluoromethyl-4-nitrophenoxy)-7-methoxyquinoline

The title compound (1.2 g) was obtained from7-methoxy-4-chloroquinoline-6-carboxyamide (900 mg) and4-nitro-3-(trifluoromethyl)phenol, in the same manner as ProductionExample 7.

¹H-NMR (DMSO-d₆) δ (ppm) 4.03 (3H, s), 6.91 (1H, d, J=5.2 Hz), 7.57 (1H,s), 7.72-7.87 (3H, m), 8.01-8.05 (1H, m), 8.27-8.32 (1H, m), 8.58 (1H,s), 8.75-8.79 (1H, m)

Production Example 489-24-(6-Carbamoyl-7-methoxy-4-quinolyl)oxy-2-trifluoromethylphenylamine

After dissolving6-carbamoyl-4-(3-trifluoromethyl-4-nitrophenoxy)-7-methoxyquinoline(0.60 g) in tetrahydrofuran (10 ml) and methanol (10 ml), the solutionwas subjected to catalytic reduction with palladium-carbon (600 mg) for10 hours under a hydrogen atmosphere to obtain the title compound (0.60g).

¹H-NMR (DMSO-d₆) δ (ppm) 4.00 (3H, s), 5.71 (2H, brs), 6.42 (1H, d,J=5.2 Hz), 6.93-6.98 (1H, m), 7.23-7.30 (2H, m), 7.46-7.52 (1H, m), 7.71(1H, brs), 7.83 (1H, brs), 8.60-8.69 (2H, m)

Production Example 489-3[4-(6-Carbamoyl-7-methoxy-4-quinolyl)oxy-2-trifluoromethylphenyl]carbamicacid phenyl ester

The title compound was obtained from4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2-trifluoromethyl-phenylamine,by the method described in Production Example 141-1.

H-NMR(CDCl₃) δ (ppm) 4.12 (3H, s), 5.90 (1H, brs), 6.48 (1H, d, J=5.6Hz), 7.20-7.30 (4H, m), 7.38-7.51 (3H, m), 7.56 (1H, s), 7.80 (1H, brs),8.27-8.31 (1H, m), 8.70 (1H, d, J=5.2 Hz), 9.26 (1H, s)

Example 490N-[4-(6-Carbamoyl-7-methoxy-4-quinolyl)oxy-2,3-dimethylphenyl]-N′-cyclopropylurea

Cyclopropylamine (0.10 ml) was added to dimethylsulfoxide (3.0 ml), andthen[4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy)-2,3-dimethylphenyl]carbamicacid phenyl ester (120 mg) was dissolved therein and the mixture wasstirred for 10 minutes. Water and ethyl acetate were added to thereaction solution and the precipitated crystals were filtered out toobtain the title compound (60 mg).

¹H-NMR (DMSO-d₆) δ (ppm) 0.37-0.44 (2H, m), 0.60-0.65 (2H, m), 2.01 (3H,s), 2.14 (3H, s), 4.01 (3H, s), 6.23 (1H, d, J=5.2 Hz), 6.64-6.69 (1H,m), 6.98 (1H, d, J=8.8 Hz), 7.50 (1H, s), 7.60-7.69 (2H, m), 7.73 (1H,brs), 7.85 (1H, brs), 8.60 (1H, d, 5.2 Hz), 8.71 (1H, s)

The starting material was synthesized by the following 2 steps.

Production Example 490-14-(6-Carbamoyl-7-methoxy-4-quinolyl)oxy-2,3-dimethylphenylamine

The title compound (840 mg) was obtained from7-methoxy-4-chloroquinoline-6-carboxyamide (890 mg) and4-nitro-2,3-dimethylphenol (940 mg), in the same manner as ProductionExample 7. Next,6-carbamoyl-4-(2,3-dimethyl-4-nitrophenoxy)-7-methoxyquinoline (840 mg)was dissolved in tetrahydrofuran (25 ml) and methanol (25 ml), and thesolution was subjected to catalytic reduction with palladium-carbon (840mg) for 10 hours under a hydrogen atmosphere to obtain the titlecompound (639 mg).

¹H-NMR (DMSO-d₆) δ (ppm) 1.92 (3H, s), 2.02 (3H, s) 4.00 (3H, s),4.82-4.88 (2H, m), 6.22 (1H, d, J=5.2 Hz), 6.60 (1H, d, J=8.4 Hz), 6.75(1H, d, J=8.4 Hz), 7.471H, s), 7.71 (1H, brs), 7.84 (1H, brs), 8.57 (1H,d, J=5.2 Hz), 8.70 (1H, s)

Production Example 490-2[4-(6-Carbamoyl-7-methoxy-4-quinolyl)oxy-2,3-dimethylphenyl]carbamicacid phenyl ester

The title compound was obtained from4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2,3-dimethylphenylamine, by themethod described in Production Example 141-1.

¹H-NMR(CDCl₃-d₆) δ (ppm) 2.13 (3H, s), 2.33 (3H, s), 4.13 (3H, s), 5.88(1H, brs), 6.29 (1H, d, J=5.6 Hz), 6.98-7.01 (1H, m), 7.20-7.25 (4H, m),7.38-7.42 (2H, m), 7.54 (1H, s), 7.70 (1H, brs), 7.80 (1H, brs), 8.60(1H, d, J=5.6 Hz), 9.36 (1H, s)

Example 491N-[4-(6-Carbamoyl-7-methoxy-4-quinolyl)oxy)-2,5-dimethylphenyl]-N′-cyclopropylurea

Cyclopropylamine (0.06 ml) was added to dimethylsulfoxide (2.0 ml), andthen[4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy)-2,5-dimethylphenyl]carbamicacid phenyl ester (100 mg) was dissolved therein and the mixture wasstirred for 10 minutes. Water and ethyl acetate were added to thereaction solution and the precipitated crystals were filtered out toobtain the title compound (60 mg).

¹H-NMR (DMSO-d₆) δ (ppm) 0.40-0.44 (2H, m), 0.63-0.67 (2H, m), 2.04 (3H,s), 2.17 (3H, s), 2.53-2.60 (1H, m), 4.03 (3H, s), 6.29 (1H, d, J=5.2Hz), 6.75-6.78 (1H, m), 7.02 (1H, s), 7.51 (1H, s), 7.58 (1H, s), 7.74(1H, brs), 7.83-7.88 (2H, m), 8.62 (1H, d, 5.2 Hz), 8.72 (1H, s)

The starting material was synthesized by the following 2 steps.

Production Example 491-14-(6-Carbamoyl-7-methoxy-4-quinolyl)oxy-2,5-dimethylphenylamine

4-Amino-2,5-dimethylphenol (1.0 g) was dissolved in dimethylsulfoxide (5ml), and then 60% sodium hydride (1.0 g) was added and the mixture wasstirred for a while. After adding7-methoxy-4-chloroquinoline-6-carboxyamide (900 mg), the mixture washeated at 100° C. for 6 hours. Water was added to the reaction solution,extraction was performed with ethyl acetate, and then the organic layerwas washed with water and saturated brine in that order and dried overanhydrous sodium sulfate, and the solvent was distilled off underreduced pressure. The obtained crude product was washed with ethylacetate to obtain the title compound (135 mg).

¹H-NMR (DMSO-d₆) δ (ppm) 1.91 (3H, s), 2.03 (3H, s), 4.01 (3H, s), 6.26(1H, d, J=5.2 Hz), 6.57 (1H, s), 6.77 (1H, s), 7.46 (1H, s), 7.70 (1H,brs), 7.83 (1H, brs), 8.57 (1H, d, J=5.2 Hz), 8.69 (1H, s)

Production Example 491-2[4-(6-Carbamoyl-7-methoxy-4-quinolyl)oxy-2,5-dimethylphenyl]carbamicacid phenyl ester

The title compound was obtained from4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2,5-dimethylphenylamine, by themethod described in Production Example 141-1.

¹H-NMR(CDCl₃) δ (ppm) 2.13 (3H, s), 2.33 (3H, s), 4.13 (3H, s), 5.88(1H, brs), 6.30 (1H, d, J=5.6 Hz), 6.75 (1H, brs), 6.94 (1H, s),7.18-7.32 (3H, m), 7.38-7.45 (2H, m), 7.54 (1H, s), 7.82 (2H, brs), 8.62(1H, d, J=5.6 Hz), 9.32 (1H, s)

Example 492N-{4-[6-Cyano-7-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)quinolin-4-yloxy]-2-fluorophenyl}-N′-(4-fluorophenyl)urea

After adding tetrahydrofuran (1 ml) and pyrrolidine (0.1 ml) toN-[4-(6-cyano-7-oxiranylmethoxyquinolin-4-yloxy)-2-fluorophenyl]-N′-(4-fluorophenyl)urea(100 mg), the mixture was heated at 50° C. for 30 minutes. The reactionsolution was purified by NH silica gel column chromatography (ethylacetate-methanol system) to obtain the title compound (45 mg) as lightyellow crystals.

¹H-NMR (DMSO-d₆) δ (ppm): 1.60-1.70 (4H, m), 2.40-2.75 (6H, m),3.95-4.05 (1H, m), 4.20 (1H, dd, J=10, 6.0 Hz), 4.30 (1H, dd, J=10, 4Hz), 5.02 (1H, d, J=4.4 Hz), 6.61 (1H, d, J=5.2), 7.10-7.17 (3H, m),7.35-7.50 (3H, m), 7.62 (1H, s), 8.21-8.27 (1H, m), 8.62-8.64 (1H, m),8.72-8.75 (2H, m), 9.09 (1H, brs)

The starting material was synthesized by the following 2 steps.

Production Example 492-14-(4-Amino-3-fluorophenoxy)-7-oxiranylmethoxyquinoline-6-carbonitrile

After adding dimethylformamide (6 ml), epibromohydrin (1.3 ml) andpotassium carbonate (380 mg) to4-(4-amino-3-fluorophenoxy)-6-cyano-7-hydroxyquinoline (400 mg), themixture was stirred overnight at room temperature. Water was added tothe reaction solution, extraction was performed with ethyl acetate, andthen the organic layer was washed with water and saturated brine in thatorder and dried over anhydrous sodium sulfate, and the solvent wasdistilled off under reduced pressure to obtain the title compound (400mg).

¹H-NMR (DMSO-d₆) δ (ppm): 2.79-2.93 (2H, m), 3.42-3.49 (1H, m), 4.15(1H, dd, J=12, 7.2 Hz), 4.69 (1H, dd, J=12, 2.4 Hz), 5.25 (2H, brs),6.53 (1H, d, J=5.2), 6.83-6.89 (2H, m), 7.07-7.15 (1H, m), 7.61 (1H, s),8.69-8.74 (2H, m)

Production Example 492-2N-[4-(6-Cyano-7-oxiranylmethoxyquinolin-4-yloxy)-2-fluorophenyl]-N′-(4-fluorophenyl)urea

After adding dimethylformamide (2 ml) and 4-fluorophenyl isocyanate(0.15 ml) to4-(4-amino-3-fluorophenoxy)-7-oxiranylmethoxy-quinoline-6-carbonitrile(400 mg), the mixture was stirred overnight at room temperature. Waterwas added to the reaction solution and the precipitated crystals werefiltered off to obtain the title compound (480 mg) as light yellowcrystals.

¹H-NMR (DMSO-d₆) δ (ppm): 2.79-2.95 (2H, m), 3.40-3.50 (1H, m),4.10-4.20 (1H, m), 4.65-4.76 (1H, m) 6.62 (1H, d, J=6.0 Hz), 7.05-7.18(3H, m), 7.36-7.50 (3H, m), 7.62 (1H, s), 8.20-8.28 (1H, m), 8.60-8.68(1H, m), 8.73-8.80 (2H, m), 9.10 (1H, brs)

Example 493N-{4-[6-Cyano-7-(3-diethylamino-2-hydroxypropoxy)quinolin-4-yloxy]-2-fluorophenyl}-N′-(4-fluorophenyl)urea

After adding tetrahydrofuran (1 ml) and diethylamine (0.1 ml) to

N-[4-(6-cyano-7-oxiranylmethoxyquinolin-4-yloxy)-2-fluorophenyl]-N′-(4-fluorophenyl)urea(100 mg), the mixture was heated at 50° C. for 30 minutes. The reactionsolution was purified by NH silica gel column chromatography (ethylacetate-methanol system) to obtain the title compound (32 mg) as lightyellow crystals.

¹H-NMR (DMSO-d₆) δ (ppm): 0.958 (6H, t, J=7 Hz), 2.40-2.68 (6H, m),3.91-3.99 (1H, m), 4.20 (1H, dd, J=10, 5.2 Hz), 4.31 (1H, dd, J=10, 3.6Hz), 4.91 (1H, d, J=4.4 Hz), 6.61 (1H, d, J=5.2 Hz), 7.10-7.17 (3H, m),7.37-7.49 (3H, m), 7.62 (1H, s), 8.21-8.27 (1H, m), 8.63 (1H, brs),8.72-8.75 (2H, m), 9.10 (1H, brs)

Example 494N-{4-[6-Cyano-7-(2-hydroxy-(3-morpholin-4-yl)propoxy)quinolin-4-yloxy]-2-fluorophenyl}-N′-(4-fluorophenyl)urea

After adding tetrahydrofuran (1 ml) and morpholine (0.1 ml) toN-[4-(6-cyano-7-oxiranylmethoxyquinolin-4-yloxy)-2-fluorophenyl]-N′-(4-fluorophenyl)urea(100 mg), the mixture was heated at 50° C. for 30 minutes. The reactionsolution was purified by NH silica gel column chromatography (ethylacetate-methanol system) to obtain the title compound (32 mg) as lightyellow crystals.

¹H-NMR (DMSO-d₆) δ (ppm): 2.38-2.58 (6H, m), 3.53-3.59 (4H, m),4.03-4.09 (1H, m), 4.22 (1H, dd, J=10, 6.0 Hz), 4.31 (1H, dd, J=10, 4.0Hz), 5.03 (1H, d, J=4.8), 6.61 (1H, d, J=5.2 Hz), 7.10-7.17 (3H, m),7.36-7.49 (3H, m), 7.64 (1H, s), 8.20-8.27 (1H, m), 8.60-8.64 (1H, m),8.73-8.75 (2H, m), 9.10 (1H, brs)

Example 495N-{4-[6-Cyano-7-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)guinolin-4-yloxy]-2-fluorophenyl}-N′-(thiazol-2-yl)urea

After adding tetrahydrofuran (1 ml) and pyrrolidine (0.1 ml) toN-[4-(6-cyano-7-oxiranylmethoxy-quinolin-4-yloxy)-2-fluorophenyl]-N′-(thiazol-2-yl)urea(120 mg), the mixture was heated at 50° C. for 40 minutes. The reactionsolution was purified by NH silica gel column chromatography (ethylacetate-methanol system) to obtain the title compound (70 mg) as lightyellow crystals.

¹H-NMR (DMSO-d₆) δ (ppm): 1.60-1.70 (4H, m), 2.40-2.75 (6H, m),3.95-4.05 (1H, m), 4.20 (1H, dd, J=10, 6.0 Hz), 4.31 (1H, dd, J=10, 4Hz), 5.02 (1H, brs), 6.62 (1H, d, J=5.2 Hz), 6.85 (1H, s), 7.10-7.20(2H, m), 7.37-7.47 (2H, m), 7.62 (1H, s), 8.20-8.26 (1H, m), 8.71-8.76(2H, m), 9.05 (1H, brs)

The starting material was synthesized in the following manner.

Production Example 495-1N-[4-(6-Cyano-7-oxiranylmethoxyquinolin-4-yloxy)-2-fluorophenyl]-N′-(thiazol-2-yl)urea

After adding dimethylsulfoxide (1 ml) and phenylN-(2-thiazolyl)carbamate (94 mg) to4-(4-amino-3-fluorophenoxy)-7-oxiranylmethoxyquinoline-6-carbonitrile(100 mg), the mixture was heated at 80° C. for 90 minutes. Water wasadded and the precipitated crystals were filtered out to obtain thetitle compound (16 mg) as light yellow crystals.

¹H-NMR (DMSO-d₆) δ (ppm): 2.78-2.94 (2H, m), 3.41-3.49 (1H, m), 4.17(1H, dd, J=12, 6.4 Hz), 4.71 (1H, dd, J=12, 2.0), 6.64 (1H, d, J=5.2Hz), 7.08-7.20 (3H, m), 7.36-7.48 (2H, m), 7.65 (1H, s), 8.20-8.27 (1H,m), 8.73-8.79 (2H, m), 9.07 (1H, brs)

Example 496N-{4-[6-Cyano-7-(2-hydroxy-3-(piperidin-1-yl)propoxy)quinolin-4-yloxy]-2-fluorophenyl}-N′-(4-fluorophenyl)urea

After adding tetrahydrofuran (1.5 ml) and piperidine (0.08 ml) toN-[4-(6-cyano-7-oxiranylmethoxyquinolin-4-yloxy)-2-fluorophenyl]-N′-(4-fluorophenyl)urea(78 mg), the mixture was heated at 50° C. for 30 minutes. The reactionsolution was purified by NH silica gel column chromatography (ethylacetate-methanol system) to obtain the title compound (32 mg) as lightyellow crystals.

¹H-NMR (DMSO-d₆) δ (ppm): 1.30-1.55 (6H, m), 2.35-2.55 (6H, m),4.00-4.08 (1H, m), 4.20 (1H, dd, J=10, 6.0 Hz), 4.30 (1H, dd, J=10, 4.0Hz), 4.94 (1H, d, J=4.8 Hz), 6.61 (1H, d, J=5.6 Hz), 7.10-7.17 (3H, m),7.36-7.50 (3H, m), 7.63 (1H, m), 8.20-8.23 (1H, m), 8.62-8.64 (1H, m),8.72-8.75 (2H, m), 9.10 (1H, m)

Example 497N-(4-{6-Cyano-7-[(2R)-2-hydroxy-3-(piperidin-1-yl)propoxy]quinolin-4-yloxy}-2-fluorophenyl)-N′-(4-fluorophenyl)urea

The title compound (115 mg) was obtained as light yellow crystals fromN-(4-{6-cyano-7-[(2R)-oxiran-2-yl]methoxyquinolin-4-yloxy}-2-fluorophenyl)-N′-(4-fluorophenyl)urea(345 mg), by the same procedure as in Example 496.

¹H-NMR (DMSO-d₆) δ (ppm): H-NMR (DMSO-d₆) δ (ppm): 1.30-1.55 (6H, m),2.35-2.55 (6H, m), 4.00-4.08 (1H, m), 4.20 (1H, dd, J=10, 6.0 Hz), 4.30(1H, dd, J=10, 4.0 Hz), 4.94 (1H, d, J=4.8 Hz), 6.61 (1H, d, J=5.6 Hz),7.10-7.17 (3H, m), 7.36-7.50 (3H, m), 7.63 (1H, m), 8.20-8.23 (1H, m),8.62-8.64 (1H, m), 8.72-8.75 (2H, m), 9.10 (1H, m)

The starting material was synthesized by the following 2 steps.

Production Example 497-14-(4-Amino-3-fluoro-phenoxy)-7-[(2R)-oxiran-2-yl]methoxyquinoline-6-carbonitrile

After adding dimethylformamide (8 ml), (2R)-(−)-glycidylp-toluenesulfonate (1000 mg) and potassium carbonate (940 mg) to4-(4-amino-3-fluorophenoxy)-6-cyano-7-hydroxyquinoline (1000 mg), themixture was heated at 50° C. for 4 hours. Water was added to thereaction solution, extraction was performed with ethyl acetate, and thenthe organic layer was washed with water and saturated brine in thatorder and dried over anhydrous sodium sulfate, and the solvent wasdistilled off under reduced pressure. The obtained crude product waspurified by silica gel column chromatography (ethyl acetate) to obtainthe title compound (659 mg) as light yellow crystals.

¹H-NMR (DMSO-d₆) δ (ppm): 2.79-2.93 (2H, m), 3.42-3.49 (1H, m), 4.15(1H, dd, J=12, 7.2 Hz), 4.69 (1H, dd, J=12, 2.4 Hz), 5.25 (2H, brs),6.53 (1H, d, J=5.2 Hz), 6.83-6.89 (2H, m), 7.07-7.15 (1H, m), 7.61 (1H,s), 8.69-8.74 (2H, m)

Production Example 497-2N-(4-{6-Cyano-7-[(2R)-oxiran-2-yl]methoxyquinolin-4-yloxy}-2-fluorophenyl)-N′-(4-fluorophenyl)urea

The title compound (200 mg) was obtained from4-(4-amino-3-fluorophenoxy)-7-[(2R)-oxiran-2-yl]methoxyquinoline-6-carbonitrile(150 mg), by the method described in Production Example 492-1.

¹H-NMR (DMSO-d₆) δ (ppm): 2.79-2.95 (2H, m), 3.40-3.50 (1H, m),4.10-4.20 (1H, m), 4.65-4.76 (1H, m) 6.62 (1H, d, J=6.0 Hz), 7.05-7.18(3H, m), 7.36-7.50 (3H, m), 7.62 (1H, s), 8.20-8.28 (1H, m), 8.60-8.68(1H, m), 8.73-8.80 (2H, m), 9.10 (1H, brs)

Example 498N-(4-{6-Cyano-7-[3-diethylamino-(2R)-2-hydroxy-propoxy]-quinolin-4-yloxy}-2-fluorophenyl)-N′-(4-fluorophenyl)urea

The title compound (120 mg) was obtained as light yellow crystals from

N-(4-{6-cyano-7-[(2R)-oxiran-2-yl]methoxyquinolin-4-yloxy}-2-fluorophenyl)-N′-(4-fluorophenyl)urea(200 mg), by the same procedure as in Example 493.

¹H-NMR (DMSO-d₆) δ (ppm): 0.96 (6H, t, J=7 Hz), 2.40-2.68 (6H, m),3.91-3.99 (1H, m), 4.20 (1H, dd, J=10, 5.2 Hz), 4.31 (1H, dd, J=10, 3.6Hz), 4.91 (1H, d, J=4.4 Hz), 6.61 (1H, d, J=5.2 Hz), 7.10-7.17 (3H, m),7.37-7.49 (3H, m), 7.62 (1H, s), 8.21-8.27 (1H, m), 8.63 (1H, brs),8.72-8.75 (2H, m), 9.10 (1H, brs)

Example 499N-(4-{6-Cyano-7-[3-dimethylamino-(2R)-2-hydroxy-propoxy]-quinolin-4-yloxy}-2-fluorophenyl)-N′-(4-fluorophenyl)urea

After adding tetrahydrofuran (0.5 ml) and a dimethylamine-2Ntetrahydrofuran solution (Aldrich, 0.2 ml) toN-(4-{6-cyano-7-[(2R)-oxiran-2-yl]methoxyquinolin-4-yloxy}-2-fluorophenyl)-N′-(4-fluorophenyl)urea(40 mg), the mixture was stirred overnight at room temperature. Thereaction solution was purified by NH silica gel column chromatography(ethyl acetate-methanol system) to obtain the title compound (45 mg) aslight yellow crystals.

¹H-NMR (DMSO-d₆) δ (ppm): 2.20 (6H, m), 2.30-2.58 (2H, m), 3.95-4.95(1H, m), 4.19 (1H, dd, J=10, 5.6 Hz), 4.29 (1H, dd, J=10, 4.0 Hz), 4.99(1H, d, J=4.4 Hz), 6.61 (1H, d, J=5.6 Hz), 7.10-7.17 (3H, m), 7.37-7.50(3H, m), 7.62 (1H, s), 8.20-8.30 (1H, m), 8.64 (1H, brs), 8.70-8.76 (2H,m), 9.11 (1H, brs)

Example 500N-(4-{6-Cyano-7-[3-diethylamino-(2R)-2-hydroxy-propoxy]-quinolin-4-yloxy}-2-fluorophenyl)-N′-(thiazol-2-yl)urea

After adding tetrahydrofuran (4 ml) and diethylamine (0.2 ml) to

N-(4-{6-cyano-7-[(2R)-oxiran-2-yl]methoxyquinolin-4-yloxy}-2-fluorophenyl)-N′-(thiazol-2-yl)urea(200 mg), the mixture was stirred at 50° C. for 2 hours. The reactionsolution was purified by NH silica gel column chromatography (ethylacetate-methanol system) to obtain the title compound (60 mg) as lightyellow crystals.

¹H-NMR (DMSO-d₆) δ (ppm): 0.96 (6H, t, J=7.0 Hz), 2.40-2.70 (6H, m),3.90-3.98 (1H, m), 4.21 (1H, dd, J=10, 5.2 Hz), 4.31 (1H, dd, J=10, 3.2Hz), 4.90-4.95 (1H, m), 6.62 (1H, d, J=5.2 Hz), 7.11-7.20 (2H, m),7.36-7.47 (2H, m), 7.62 (1H, s), 8.20-8.27 (1H, m), 8.72-8.76 (2H, m)

The starting material was synthesized in the following manner.

Production Example 500-1N-(4-{6-Cyano-7-[(2R)-oxiran-2-yl]methoxyquinolin-4-yloxy}-2-fluorophenyl)-N′-(thiazol-2-yl)urea

The title compound (370 mg) was obtained as light yellow crystals from4-(4-amino-3-fluorophenoxy)-7-[(2R)-oxiran-2-yl]methoxyquinoline-6-carbonitrile(300 mg), by the method described in Example 495.

H-NMR (DMSO-d₆) δ (ppm): 2.78-2.94 (2H, m), 3.41-3.49 (1H, s), 4.17 (1H,dd, J=12, 6.4 Hz), 4.71 (1H, dd, J=12, 2.0 Hz), 6.64 (1H, d, J=5.2 Hz),7.08-7.20 (2H, m), 7.36-7.48 (2H, m), 7.65 (1H, s), 8.20-8.27 (1H, m),8.73-8.79 (2H, m), 9.07 (1H, brs)

Example 501N-(2-Fluoro-4-{[6-cyano-7-(4-piperidylmethoxy)-4-quinolyl]oxy}phenyl)-N′-(4-fluorophenyl)urea

After dissolving4-(6-cyano-4-{3-fluoro-4-[3-(4-fluorophenyl)ureido]phenoxy}quinolin-7-yloxymethyl)piperidine-1-carboxylicacid tert-butyl ester (395 mg) in trifluoroacetic acid (2 ml), thesolution was stirred for 10 minutes at room temperature. Water (20 ml)was added, the mixture was neutralized with sodium bicarbonate, and theprecipitated crystals were filtered out to obtain the title compound(260 mg).

¹H-NMR (DMSO-d₆) δ (ppm): 1.15-1.30 (2H, m), 1.69-1.76 (2H, m),1.85-2.00 (1H, m), 2.44-2.70 (2H, m), 2.90-2.99 (2H, m), 4.09-4.25 (3H,m), 6.61 (1H, d, J=5.2 Hz), 7.05-7.14 (3H, m), 7.34-7.40 (1H, m),7.48-7.55 (2H, m), 7.59 (1H, s), 8.10-8.17 (1H, m), 8.70-8.76 (2H, m)

The starting material was synthesized by the following 3 steps.

Production Example 501-14-[4-(4-Amino-3-fluorophenoxy)-6-cyanoquinolin-7-yloxymethyl]-piperidine-1-carboxylicacid tert-butyl ester

After adding dimethylformamide (4 ml), tert-butyl4-(bromomethyl)-1-piperidine carboxylate (708 mg) and potassiumcarbonate (467 mg) to4-(4-amino-3-fluorophenoxy)-6-cyano-7-hydroxyquinoline (500 mg), themixture was heated at 50° C. for 4 hours. Water was added to thereaction solution, extraction was performed with ethyl acetate and theorganic layer was washed with water and saturated brine in that orderand then dried over anhydrous sodium sulfate, and the solvent wasdistilled off under reduced pressure. The obtained crude product waspurified by silica gel column chromatography (n-hexane:ethyl acetate) toobtain the title compound (398 mg).

¹H-NMR (DMSO-d₆) δ (ppm): 1.16-1.31 (2H, m), 1.39 (9H, s), 1.72-1.82(2H, m), 2.00-2.08 (1H, m), 2.65-2.83 (2H, m), 3.93-4.03 (2H, m),4.11-4.18 (2H, m), 5.20-5.26 (2H, m), 6.50 (1H, d, J=5.2 Hz), 6.82-6.85(2H, m), 7.02-7.10 (1H, m), 7.56 (1H, s), 8.65-8.72 (2H, m)

Production Example 501-24-(6-Cyano-4-{3-fluoro-4-[3-(4-fluorophenyl)ureido]phenoxy}quinolin-7-yloxymethyl)piperidine-1-carboxylicacid tert-butyl ester

The title compound (500 mg) was obtained as light yellow crystals from4-[4-(4-amino-3-fluorophenoxy)-6-cyanoquinolin-7-yloxymethyl]piperidine-1-carboxylicacid tert-butyl ester (619 mg) and 4-fluorophenyl isocyanate (0.22 ml),by the same procedure as in Example 492.

¹H-NMR (DMSO-d₆) δ (ppm): 1.20-1.35 (2H, m), 1.39 (9H, s), 1.73-1.85(2H, m), 2.00-2.10 (1H, m), 2.63-2.86 (2H, m), 3.92-4.06 (2H, m),4.13-4.20 (2H, m), 6.61 (1H, d, J=5.6 Hz), 7.10-7.16 (3H, m) 7.36-7.50(3H, m), 7.60 (1H, s), 8.20-8.28 (1H, m), 8.68-8.76 (2H, m), 9.27 (1H,brs)

Example 502N-{4-[6-Cyano-7-(1-methylpiperidin-4-yl)methoxyquinolin-4-yloxy]-2-fluorophenyl}-N′-(4-fluorophenyl)urea

After dissolvingN-(2-fluoro-4-{[6-cyano-7-(4-piperidinomethoxy)-4-quinolyl]oxy}phenyl)-N′-(4-fluorophenyl)urea(180 mg) in tetrahydrofuran (10 ml)-methanol (10 ml), there were added37% aqueous formaldehyde (0.5 ml), acetic acid (0.04 ml) and sodiumcyanoborohydride (43 mg) at room temperature, and the mixture wasstirred for 1 hour. The reaction solution was distributed between ethylacetate and saturated aqueous sodium bicarbonate, and the organic layerwas washed with saturated brine and dried over anhydrous sodium sulfate.The solvent was distilled off, and after suspension in ethyl acetate anddilution with hexane, the crystals were filtered out and blow-dried toobtain the title compound (130 mg) as white crystals.

¹H-NMR (DMSO-d₆) δ (ppm): 1.13-1.47 (2H, m), 1.73-1.92 (5H, m), 2.15(3H, s), 2.77-2.85 (2H, m), 4.13-4.16 (2H, m), 6.61 (1H, d, J=5.6 Hz),7.10-7.16 (3H, m), 7.36-7.49 (3H, m), 7.59 (1H, s), 8.20-8.26 (1H, m),8.62-8.68 (1H, m), 8.72-8.76 (2H, m), 9.08-9.15 (1H, m)

Example 503N-{4-[6-Cyano-7-(piperidin-4-ylmethoxy)quinolin-4-yloxy]-2-fluorophenyl}-N′-(2-thiazolyl)urea

The title compound (240 mg) was obtained from4-{6-cyano-4-[3-fluoro-4-(3-(thiazol-2-yl)ureido)phenoxy]quinolin-7-yloxymethyl}piperidine-1-carboxylicacid tert-butyl ester (370 mg), by the same procedure as in Example 501.

¹H-NMR (DMSO-d₆) δ (ppm): 1.45-1.56 (2H, m), 1.92-2.00 (2H, m),2.13-2.23 (1H, m), 2.45-2.50 (2H, m), 2.85-2.98 (2H, m), 4.18-4.23 (2H,m), 6.64 (1H, d, J=5.2 Hz), 7.14-7.19 (2H, m), 7.37-7.47 (2H, m), 7.65(1H, s), 8.21-8.28 (1H, m), 8.74-8.79 (2H, m), 9.06 (1H, brs)

The starting material was synthesized in the following manner.

Production Example 503-14-{6-Cyano-4-[3-fluoro-4-(3-(thiazol-2-yl)ureido)phenoxy]quinolin-7-yloxymethyl}piperidine-1-carboxylicacid tert-butyl ester

This was synthesized from4-[4-(4-amino-3-fluorophenoxy)-6-cyanoquinolin-7-yloxymethyl]piperidine-1-carboxylicacid tert-butyl ester, by the method described for the intermediatesynthesis in Example 495.

¹H-NMR (DMSO-d₆) δ (ppm): 1.18-1.32 (2H, m), 1.39 (9H, s), 1.73-1.83(2H, m), 2.00-2.10 (1H, m), 2.63-2.86 (2H, m), 3.95-4.05 (2H, m),4.13-4.20 (2H, m), 6.62 (1H, d, J=5.2 Hz), 7.10-7.20 (2H, m), 7.36-7.47(2H, m), 7.61 (1H, s), 8.20-8.27 (1H, m), 8.72-8.77 (2H, m)

Example 504N-{4-[6-Cyano-7-(1-methylpiperidin-4-ylmethoxy)quinolin-4-yloxy]-2-fluorophenyl}-N′-(2-thiazolyl)urea

The title compound was obtained fromN-{4-[6-cyano-7-(piperidin-4-ylmethoxy)quinolin-4-yloxy]-2-fluorophenyl}-N′-(2-thiazolyl)urea,by the method described in Example 502.

¹H-NMR (DMSO-d₆) δ (ppm): 1.30-1.46 (2H, m), 1.70-1.93 (5H, m), 2.15(3H, s), 2.77-2.85 (2H, m), 4.13-4.17 (2H, m), 6.62 (1H, d, J=5.2 Hz),7.12-7.19 (2H, m), 7.37-7.47 (2H, m), 7.60 (1H, s), 8.20-8.30 (1H, m),8.73-8.76 (2H, m)

Example 505N-{4-[6-Cyano-7-(1-methylpiperidin-3-ylmethoxy)quinolin-4-yloxy]-2-fluorophenyl}-N′-(2-thiazolyl)urea

The title compound was obtained from4-(4-amino-3-fluorophenoxy)-7-(1-methylpiperidin-3-ylmethoxy)quinoline-6-carbonitrileby the method described for the intermediate synthesis in Example 495.

¹H-NMR (DMSO-d₆) δ (ppm): 1.10-1.20 (1H, m), 1.43-1.96 (5H, m),2.05-2.15 (1H, m), 2.16 (3H, s), 2.61-2.67 (1H, m), 2.80-2.87 (1H, m),4.15-4.19 (2H, m), 6.62 (1H, d, J=5.6 Hz), 7.12-7.20 (2H, m), 7.37-7.47(2H, m), 7.60 (1H, s), 8.20-8.26 (1H, m), 8.72-8.77 (2H, m)

The starting material was synthesized in the following manner.

Production Example 505-14-(4-Amino-3-fluorophenoxy)-7-(1-methylpiperidin-3-ylmethoxy)quinoline-6-carbonitrile

After adding dimethylformamide (4 ml), 3-chloromethyl-1-methylpiperidinehydrochloride (621 mg) and potassium carbonate (840 mg) to4-(4-amino-3-fluorophenoxy)-6-cyano-7-hydroxyquinoline (400 mg), themixture was stirred at 20° C. for 3 hours. Water was added to thereaction solution, extraction was performed with ethyl acetate, theorganic layer was washed with water and saturated brine in that orderand dried over anhydrous sodium sulfate, and the solvent was distilledoff under reduced pressure. The obtained crude product was purified byNH silica gel column chromatography (ethyl acetate) to obtain the titlecompound (60 mg).

H-NMR (DMSO-d₆) 1.10-1.20 (1H, m), 1.45-1.95 (5H, m), 2.03-2.14 (1H, m),2.14 (3H, s), 2.56-2.68 (1H, m), 2.78-2.88 (1H, m), 4.12-4.18 (2H, m),5.23-5.28 (2H, m), 6.51 (1H, d, J=5.2 Hz), 6.83-6.89 (2H, m), 7.03-7.10(1H, m), 7.56 (1H, s), 8.65-8.72 (2H, m)

Example 506N-(4-[(7-Cyano-6-methoxy-4-quinolyl)oxy]phenyl)-N′-(4-fluoro-phenyl)urea

After adding toluene (5 ml), acetonitrile (1.5 ml) and 4-fluorophenylisocyanate (0.105 ml) to4-(4-aminophenoxy)-6-methoxyquinoline-7-carbonitrile (180 mg), themixture was heated to reflux for 30 minutes.

The mixture was cooled, and the precipitated crystals were filtered outand washed with toluene to obtain the title compound (230 mg) as lightyellow crystals.

¹H-NMR (DMSO-d₆) δ (ppm) 4.05 (3H, m), 6.66 (1H, d, J=5.2 Hz), 7.08-7.14(2H, m), 7.24 (2H, d, J=8.8 Hz), 7.43-7.48 (2H, m), 7.59 (2H, d, J=8.8Hz), 7.76 (1H, s), 8.54 (1H, s), 8.64 (1H, d, J=5.2 Hz), 8.74 (1H, brs),8.84 (1H, brs)

The starting material was synthesized by the following 4 steps.

Production Example 506-1 6-Methoxy-4-(4-nitrophenoxy)quinolin-7-ol

After adding trifluoroacetic acid (30 ml) and thioanisole (3 ml) to7-benzyloxy-6-methoxy-4-(4-nitrophenoxy)quinoline (4.0 g), the mixturewas heated and stirred at 70° C. for 2 hours.

After cooling the reaction solution, it was concentrated under reducedpressure, sodium bicarbonate water and methanol were added and theprecipitated crystals were filtered out. They were then washed withdiethyl ether to obtain 4.0 g of the title compound.

¹H-NMR (DMSO-d₆) δ (ppm) 3.94 (3H, s), 6.93 (1H, d, J=5.6 Hz), 7.42 (1H,s), 7.55-7.60 (3H, m), 8.40 (2H, d, J=10 Hz), 8.71 (1H, d, J=6 Hz)

Production Example 506-2 Trifluoromethanesulfonic acid6-methoxy-4-(4-nitrophenoxy)quinolin-7-yl ester

After dissolving 6-methoxy-4-(4-nitrophenoxy)quinolin-7-ol (1.0 g) indimethylformamide (10 ml), there were added trifluoromethanesulfonicacid 4-nitrophenyl ester (640 mg) and potassium carbonate (1.3 g), andthe mixture was stirred at room temperature for 5 hours. Water wasadded, extraction was performed with ethyl acetate, the organic layerwas washed with water and saturated brine in that order and dried overanhydrous sodium sulfate, and the solvent was distilled off underreduced pressure. Ethyl acetate was used for recrystallization to obtainthe title compound (1.0 g).

¹H-NMR (DMSO-d₆) δ (ppm) 4.04 (3H, s), 7.01 (1H, d, J=4.8 Hz), 7.52-7.57(2H, m), 7.80 (1H, s), 8.18 (1H, s), 8.34-8.39 (2H, m), 8.72-8.76 (1H,m)

Production Example 506-36-Methoxy-4-(4-nitrophenoxy)quinoline-7-carbonitrile

After dissolving trifluoromethanesulfonic acid6-methoxy-4-(4-nitrophenoxy)quinolin-7-yl ester (500 mg) indimethylformamide (5 ml), there were added zinc cyanide (260 mg) andtetrakistriphenylphosphine palladium (0) (130 mg) and the mixture washeated and stirred at 110° C. for 2 hours under a nitrogen atmosphere.Water was added, extraction was performed with ethyl acetate, theorganic layer was washed with water and saturated brine in that orderand dried over anhydrous sodium sulfate, and the solvent was distilledoff under reduced pressure. Ethyl acetate was used for recrystallizationto obtain the title compound (300 mg).

¹H-NMR (DMSO-d₆) δ (ppm) 4.03 (3H, s), 7.05 (1H, d, J=5.2 Hz), 7.51-7.56(2H, m), 7.68 (1H, s), 8.34-8.39 (2H, m), 8.62 (1H, s), 8.76 (1H, d,J=5.2 Hz)

Production Example 506-44-(4-Aminophenoxy)-6-methoxyquinoline-7-carbonitrile

6-Methoxy-4-(4-nitrophenoxy)quinoline-7-carbonitrile (290 mg) wassubjected to iron reduction by the same method as in Production Example10 to obtain the title compound (180 mg).

¹H-NMR (DMSO-d₆) δ (ppm) 4.05 (3H, s), 5.19 (2H, s), 6.59 (1H, d, J=5.2Hz), 6.66 (2H, d, J=8.8 Hz), 6.94 (2H, d, J=8.8 Hz), 7.73 (1H, s), 8.51(1H, s), 8.61 (1H, d, J=5.2 Hz)

Example 507N-(4-[(7-Carbamoyl-6-methoxy-4-quinolyl)oxy]phenyl)-N′-(4-fluorophenyl)urea

After dissolvingN-(4-[(7-cyano-6-methoxy-4-quinolyl)oxy]phenyl)-N′-(4-fluorophenyl)urea(43 mg) in 1.5 ml of dimethylsulfoxide at 80° C., a 5N aqueous NaOHsolution was added thereto and the mixture was heated and stirred for 2hours. The reaction solution was neutralized with 1N HCl and theprecipitated crystals were filtered out and washed with ethanol toobtain 17 mg of the title compound.

¹H-NMR (DMSO-d₆) δ (ppm) 4.00 (3H, s), 6.58 (1H, d, J=5.2 Hz), 7.06-7.14(2H, m), 7.17-7.24 (2H, m), 7.45-7.53 (2H, m), 7.55-7.67 (3H, m), 7.70(1H, brs), 7.86 (1H, brs), 8.22 (1H, s), 8.56 (1H, d, J=5.2 Hz)

Example 508N-(4-[(7-Aminomethyl-6-methoxy-4-quinolyl)oxy]phenyl)-N′-(4-fluorophenyl)ureatrifluoroacetate

The title compound (52 mg) was obtained fromN-(4-[(7-cyano-6-methoxy-4-quinolyl)oxy]phenyl)-N′-(4-fluorophenyl)urea(50 mg), by the same procedure as in Example 480.

¹H-NMR (DMSO-d₆) δ (ppm) 4.01 (3H, s), 4.21-4.26 (2H, m), 6.66 (1H, d,J=5.2 Hz), 7.08-7.15 (2H, m), 7.23 (2H, d, J=8.8 Hz), 7.43-7.50 (2H, m),7.61 (2H, d, J=8.8 Hz), 7.67 (1H, s), 8.08 (1H, s), 8.63 (1H, d, J=5.2Hz), 8.85 (1H, brs), 8.95 (1H, brs)

Example 509N-(4-[(7-Acetylaminomethyl-6-methoxy-4-quinolyl)oxy]phenyl)-N′-(4-fluorophenyl)urea

The title compound (5 mg) was obtained fromN-(4-[(7-aminomethyl-6-methoxy-4-quinolyl)oxy]phenyl)-N′-(4-fluorophenyl)ureatrifluoroacetate (30 mg), by the method described in Example 481.

¹H-NMR (DMSO-d₆) δ (ppm) 1.94 (3H, s), 3.96 (3H, s), 4.37-4.40 (2H, m),6.51 (1H, d, J=5.2 Hz), 7.08-7.14 (2H, m), 7.20 (2H, d, J=8.8 Hz),7.43-7.50 (2H, m), 7.50-7.60 (3H, m), 7.74 (1H, s), 8.39-8.45 (1H, m),8.50 (1H, d, J=5.2 Hz), 8.80 (1H, brs), 8.88 (1H, brs)

Example 5104-{4-[3-(4-Fluorophenyl)ureido]phenoxy}furo[2,3-b]pyridine-2-carboxylicacid methyl ester

After adding toluene (1 ml), acetonitrile (0.5 ml) and 4-fluorophenylisocyanate (0.02 ml) to4-(4-aminophenoxy)furo[2,3-b]pyridine-2-carboxylic acid methyl ester (28mg), the mixture was heated to reflux for 30 minutes. After cooling, theprecipitated crystals were filtered off and washed with toluene toobtain the title compound (24 mg) as light yellow crystals.

¹H-NMR (DMSO-d₆) δ (ppm) 3.87 (3H, s), 6.75 (1H, d, J=5.6 Hz), 7.08-7.14(2H, m), 7.21-7.25 (2H, m), 7.40 (1H, s), 7.43-7.48 (2H, m), 7.55-7.60(2H, m), 8.35 (1H, d, J=5.6 Hz), 8.79 (1H, brs), 8.89 (1H, brs)

The starting material was synthesized by the following 5 steps.

Production Example 510-15-[(2,2-Dimethyl-4,6-dioxo-[1,3]dioxan-5-ylidenemethyl)amino]furan-2-carboxylicacid methyl ester

Methyl 5-amino-2-furoate (4 g) by Lancaster was added to a mixedsolution of triethyl orthoformate (20 ml) and isopropyl alcohol (20 ml),and then Meldrum acid (4.5 g) was added and the mixture was heated andstirred at 100° C. for 1 hour. After cooling, the precipitated crystalswere filtered out and washed with isopropyl alcohol to obtain the titlecompound (7.8 g).

¹H-NMR(CDCl₃) δ (ppm) 1.75 (6H, s), 3.89 (3H, s), 6.04-6.09 (1H, m),7.08-7.12 (1H, m), 8.56-8.64 (1H, m), 11.4-11.6 (1H, m)

Production Example 510-24-Oxo-4,7-dihydrofuro[2,3-b]pyridine-2-carboxylic acid methyl ester

After adding5-[(2,2-dimethyl-4,6-dioxo-[1.3]dioxan-5-ylidenemethyl)amino]furan-2-carboxylicacid methyl ester (4.0 g) to

Dowtherm A (30 ml), the mixture was heated and stirred at 200° C. for 1hour. After cooling, the precipitated crystals were filtered out andwashed with diethyl ether to obtain the title compound (2.0 g).

¹H-NMR (DMSO-d₆) δ (ppm) 3.86 (3H, s), 6.77 (1H, d, J=5.6 Hz), 7.71 (1H,s), 8.18 (1H, d, J=5.6 Hz), 11.85 (1H, brs)

Production Example 510-22 4-Chloro-furo[2.3-b]pyridine-2-carboxylic acidmethyl ester

After adding thionyl chloride (8.0 ml) and dimethylformamide (0.08 ml)to 4-oxo-4,7-dihydro-furo[2.3-b]pyridine-2-carboxylic acid methyl ester(2.0 g), the mixture was heated to reflux for 1 hour. After cooling, themixture was concentrated under reduced pressure and the precipitatedcrystals were filtered out and washed with tetrahydrofuran and ethylacetate to obtain the title compound (2.1 g).

¹H-NMR (DMSO-d₆) δ (ppm) 3.92 (3H, s), 7.66 (1H, d, J=5.2 Hz), 7.86 (1H,s), 8.49 (1H, d, J=5.2 Hz)

Production Example 510-34-(4-Nitrophenoxy)furo[2.3-b]pyridine-2-carboxylic acid methyl ester

After adding N-methylpyrrolidone (4.0 ml), diisopropylethylamine (1.3ml) and para-nitrophenol (822 mg) to4-chlorofuro[2.3-b]pyridine-2-carboxylic acid methyl ester (1.0 g), themixture was heated and stirred at 140° C. for 5 hours. After cooling,water was added, extraction was performed with ethyl acetate, theorganic layer was washed with water and saturated brine in that orderand dried over anhydrous sodium sulfate, and the solvent was distilledoff under reduced pressure. Tetrahydrofuran was used forrecrystallization to obtain the title compound (70 mg).

¹H-NMR (DMSO-d₆) δ (ppm) 3.87 (3H, s), 7.04 (1H, d, J=5.6 Hz), 7.48-7.53(2H, m), 7.59 (1H, s), 8.32-8.37 (2H, m), 8.47 (1H, d, J=5.6 Hz)

Production Example 510-4 Synthesis of4-(4-Aminophenoxy)furo[2.3-b]pyridine-2-carboxylic acid methyl ester

4-(4-Nitrophenoxy)-furo[2.3-b]pyridine-2-carboxyl is acid methyl ester(70 mg) was subjected to iron reduction by the same method as inProduction Example 10 to obtain the title compound (55 mg).

¹H-NMR (DMSO-d₆) δ (ppm) 3.86 (3H, s), 5.23 (2H, brs), 6.64 (2H, d,J=8.4 Hz), 6.72 (1H, d, J=6.0 Hz), 6.93 (2H, d, J=8.4 Hz), 7.23 (1H, s),8.31 (1H, d, J=6.0 Hz)

Example 511N-(4-Fluorophenoxy)-N′-[4-(2-hydroxymethylfuro[2.3-b]pyridin-4-yloxy)phenyl]urea

After dissolving4-{4-[3-(4-fluorophenyl)ureido]phenoxy}-furo[2.3-b]pyridine-2-carboxylicacid methyl ester (13 mg) in tetrahydrofuran (3 ml), lithiumborohydride(10 mg) was added and the mixture was stirred overnight at roomtemperature. After adding a small amount of acetone, water was added,extraction was performed with ethyl acetate, the organic layer waswashed with water and saturated brine in that order and dried overanhydrous sodium sulfate, and the solvent was distilled off underreduced pressure to obtain the title compound (10 mg).

¹H-NMR (DMSO-d₆) δ (ppm) 4.52 (2H, d, J=6.0 Hz), 5.52 (1H, t, J=6.0 Hz),6.38 (1H, s), 6.69 (1H, d, J=5.6 Hz), 7.07-7.19 (4H, m), 7.43-7.49 (2H,m), 7.51-7.57 (2H, m), 8.11 (1H, d, J=5.4 Hz), 8.11 (1H, brs), 8.81 (1H,brs)

Example 512N-(4-Fluorophenyl)-N′-[4-(6-phenylfuro[2.3-d]pyrimidin-4-yloxy)phenyl]urea

After adding toluene (1 ml), acetonitrile (0.5 ml) and 4-fluorophenylisocyanate (0.03 ml) to4-(6-phenyl-furo[2.3-d]pyrimidin-4-yloxy)phenylamine (40 mg), themixture was heated to reflux for 30 minutes. After cooling, theprecipitated crystals were filtered out and washed with toluene toobtain the title compound (42 mg) as light yellow crystals.

¹H-NMR (DMSO-d₆) δ (ppm) 7.08-7.15 (2H, m), 7.23 (2H, d, J=8.4 Hz),7.43-7.57 (7H, m), 7.65 (1H, s), 7.97 (2H, d, J=8.4 Hz), 8.50 (1H, s),8.74-8.81 (2H, m)

The starting material was synthesized by the following 4 steps.

Production Example 512-1 6-Phenylfuro[2.3-d]pyrimidin-4-ylamine

After adding formamide (10 ml) and 2 drops of acetic anhydride to2-amino-5-phenyl-3-furonitrile (1.8 g) synthesized according to themethod described in J. Heterocyclic Chem., 35, 1313 (1998), the mixturewas heated and stirred at 200° C. for 2 hours. After cooling, theprecipitated crystals were filtered out and washed with diethyl ether toobtain the title compound (1.3 g).

¹H-NMR (DMSO-d₆) δ (ppm) 7.30 (1H, s), 7.35-7.41 (1H, m), 7.46-7.53 (2H,m), 7.74-7.79 (2H, m), 8.16 (1H, m)

Production Example 512-24-(4-Nitrophenoxy-6-phenyl-furo[2.3-d]pyrimidine

After adding dibromomethane (1.2 ml) and isoamyl nitrite (1.2 ml) to6-phenylfuro[2.-d]pyrimidin-4-ylamine (211 mg), the mixture was heatedand stirred at 80° C. for 30 minutes. The reaction solution wasconcentrated under reduced pressure, water was added, extraction wasperformed with ethyl acetate, the organic layer was washed with waterand saturated brine in that order and dried over anhydrous sodiumsulfate, and the solvent was distilled off under reduced pressure. Afteradding dimethylformamide (10 ml), para-nitrobenzene (222 mg) andpotassium carbonate (414 mg), the mixture was heated and stirred at 80°C. for 1 hour. Water was added to the reaction solution, extraction wasperformed with ethyl acetate, and then the organic layer was washed withwater and saturated brine in that order and dried over anhydrous sodiumsulfate, and the solvent was distilled off under reduced pressure. Ethylacetate was used for recrystallization to obtain the title compound (150mg).

¹H-NMR (DMSO-d₆) δ (ppm) 7.43-7.67 (5H, m), 7.76 (1H, s), 7.98-8.03 (2H,m), 8.34-8.39 (2H, m), 8.56 (1H, s)

Production Example 512-34-(6-Phenylfuro[2.3-d]pyrimidin-4-yloxy)phenylamine

4-(4-Nitrophenoxy-6-phenylfuro[2.3-d]pyrimidine (150 mg) was subjectedto iron reduction by the same method as in Production Example 6 toobtain the title compound (50 mg).

¹H-NMR (DMSO-d₆) 5.10 (2H, brs), 6.59-6.63 (2H, m), 6.91-6.96 (2H, m),7.42-7.56 (4H, m), 7.91-7.95 (2H, m), 8.47 (1H, s)

Example 513 6-Carboxy-7-methoxy-4-(indol-5-yloxy)quinoline

After dissolving 6-methoxycarbonyl-7-methoxy-4-(indol-5-yloxy)quinoline(400 mg) in tetrahydrofuran (5 ml), a 1.5N aqueous lithium hydroxidesolution (2.5 ml) was added and the mixture was stirred at roomtemperature for 3 hours. The reaction solution was adjusted to pH 4 with1N aqueous hydrochloric acid, and the precipitated crystals werefiltered out and washed with ethyl acetate to obtain the title compound(280 mg).

¹H-NMR (DMSO-d₆) δ (ppm) 3.94 (3H, s), 6.37 (1H, d, J=5.2 Hz), 6.43-6.47(1H, m), 6.95-7.01 (1H, m), 7.40-7.55 (4H, m), 8.55-8.61 (2H, m), 11.3(1H, brs)

The intermediate was synthesized in the following manner.

Production Example 513-16-Methoxycarbonyl-7-methoxy-4-(indol-5-yloxy)quinoline

After mixing methyl 4-chloro-7-methoxyquinoline-6-carboxylate(WO0050405, P.34, 8.5 g, 33.77 mmol), 5-hydroxyindole (7 g),diisopropylethylamine (8.9 ml) and N-methylpyrrolidone (8.9 ml), themixture was heated and stirred at 130° C. for 5 hours and then at 150°C. for 8 hours. After cooling, the solution was adsorbed onto silica geland purified with a silica gel column (hexane-ethyl acetate system).Ethanol, diethyl ether and hexane were added to the obtained yellow oil,and crystals precipitated upon standing. These were filtered out, washedwith diethyl ether and hexane and dried by aspiration to obtain lightyellow crystals (3.506 g, 10.06 mmol, 29.80%).

¹H-NMR Spectrum (DMSO-d6) δ (ppm): 3.86 (3H, s), 3.97 (3H, s), 6.38 (1H,d, J=5.2 Hz), 6.46 (1H, s), 6.98 (1H, d, J=8.8 Hz), 7.44-7.52 (4H, m),8.60-8.65 (2H, m), 11.29 (1H, s)

Example 5146-(2-Methoxyethylcarbamoyl)-7-methoxy-4-(indol-5-yloxy)quinoline

After dissolving 6-carboxy-7-methoxy-4-(indol-5-yloxy)quinoline (100 mg)in dimethylformamide (4.0 ml), there were added methoxyethylamine (0.04ml), triethylamine (0.08 ml) andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(198 mg), and the mixture was stirred at room temperature for 5 hours.Water was added to the reaction solution, extraction was performed withethyl acetate, and then the organic layer was washed with water andsaturated brine in that order and dried over anhydrous sodium sulfate,and the solvent was distilled off under reduced pressure. Ethyl acetatewas used for recrystallization to obtain the title compound (86 mg).

¹H-NMR (DMSO-d₆) δ (ppm) 3.29 (3H, s), 3.46-3.49 (4H, m), 4.02 (3H, s),6.37 (1H, d, J=5.2 Hz), 6.45-6.47 (1H, m), 6.95-7.00 (1H, m), 7.41-7.54(4H, m), 8.42-8.45 (1H, m), 8.59 (1H, d, J=5.2 Hz), 8.68 (1H, s), 11.3(1H, brs).

Example 5156-(2-Methoxyethylcarbonyl)-7-methoxy-4-(1-ethylcarbamoyl-indol-5-yloxy)quinoline

After adding 60% sodium hydride (10 mg) to dimethylformamide (1 ml), themixture was stirred at room temperature,6-(2-methoxyethylcarbamoyl)-7-methoxy-4-(indol-5-yloxy)quinoline (10 mg)was added, and the mixture was stirred for another 15 minutes.Ethylcarbamic acid phenyl ester (43 mg) was then added and the mixturewas stirred for 1 hour. Water was added to the reaction solution,extraction was performed with ethyl acetate, and then the organic layerwas washed with water and saturated brine in that order and dried overanhydrous sodium sulfate, and the solvent was distilled off underreduced pressure. Ethyl acetate was used for recrystallization to obtainthe title compound (27 mg).

¹H-NMR (DMSO-d₆) δ (ppm) 1.18 (3H, t, J=7.2 Hz), 3.27-3.29 (5H, m),3.47-3.49 (4H, m), 4.02 (3H, s), 6.42 (1H, d, J=5.2 Hz), 6.70 (1H, d,J=3.6 Hz), 7.15-7.20 (1H, m), 7.50-7.52 (2H, m), 7.93 (1H, d, J=3.6 Hz),8.20-8.50 (3H, m), 8.61 (1H, d, J=5.2 Hz), 8.67 (1H, s)

Example 5166-(2-Methoxyethylcarbonyl)-7-methoxy-4-[1-(2-fluoroethylcarbamoyl)indol)-5-yloxy]quinoline

The title compound was obtained from6-(2-methoxyethylcarbamoyl)-7-methoxy-4-(indol-5-yloxy)quinoline using2-fluoroethylcarbamic acid phenyl ester, by the same procedure as inExample 515.

¹H-NMR (DMSO-d₆) δ (ppm) 3.24 (3H, s), 3.45-3.67 (6H, m), 4.02 (3H, s),4.50-4.68 (2H, m), 6.43 (1H, d, J=5.2 Hz), 6.72 (1H, d, J=3.6 Hz),7.16-7.21 (1H, m), 7.50-7.54 (2H, m), 7.98 (1H, d, J=3.6 Hz), 8.35 (1H,d, J=9.2 Hz), 8.42-8.53 (2H, m), 8.61 (1H, d, J=5.2 Hz), 8.76 (1H, s)

Example 5176-(2-Fluoroethylcarbamoyl)-7-methoxy-4-(indol-5-yloxy)quinoline

The title compound was obtained from6-carboxy-7-methoxy-4-(indol-5-yloxy)quinoline using 2-fluoroethylaminehydrochloride, by the same procedure as in Example 514.

¹H-NMR (DMSO-d₆) δ (ppm) 3.53-3.71 (2H, m), 4.02 (3H, s), 4.48-4.63 (2H,m), 6.37 (1H, d, J=5.2 Hz), 6.45-6.47 (1H, m), 6.95-7.00 (1H, m),7.42-7.46 (2H, m), 7.48-7.53 (2H, m), 8.57-8.63 (2H, m), 8.66 (1H, s),11.6 (1H, brs)

Example 5186-(2-Fluoroethylcarbonyl)-7-methoxy-4-((1-ethylcarbamoyl)indol-5-yloxy)quinoline

The title compound was obtained from6-(2-fluoroethylcarbamoyl)-7-methoxy-4-(indol-5-yloxy)quinoline, by thesame procedure as in Example 515.

¹H-NMR (DMSO-d₆) δ (ppm) 1.18 (3H, t, J=7.2 Hz), 3.27-3.32 (2H, m),3.56-3.68 (2H, m), 4.02 (3H, s), 4.47-4.65 (2H, m), 6.42 (1H, d, J=5.2Hz), 6.70 (1H, d, J=4.0 Hz), 7.15-7.20 (1H, m) 7.50-7.52 (2H, m), 7.93(1H, d, J=4.0 Hz), 8.22-8.27 (1H, m), 8.34 (1H, d, J=8.9 Hz), 8.57-8.66(3H, m).

Example 519 6-Methoxycarbamoyl-7-methoxy-4-(indol-5-yloxy)quinoline

The title compound was obtained from6-carboxy-7-methoxy-4-(indol-5-yloxy)quinoline using methylhydroxylaminehydrochloride, by the same procedure as in Example 514.

¹H-NMR (DMSO-d₆) δ (ppm) 3.73 (3H, s), 3.98 (3H, s), 6.38 (1H, d, J=5.2Hz), 6.44-6.48 (1H, m), 6.95-7.00 (1H, m), 7.40-7.54 (4H, m), 8.49 (1H,s), 8.59 (1H, d, J=5.2 Hz), 11.29 (1H, brs), 11.45 (1H, brs)

Example 5206-Methoxycarbamoyl-7-methoxy-4-((1-ethylcarbamoyl)indol-5-yloxy)quinoline

The title compound was obtained from6-methoxycarbamoyl-7-methoxy-4-(indol-5-yloxy)quinoline, by the sameprocedure as in Example 515.

¹H-NMR (DMSO-d₆) δ (ppm) 1.16 (3H, t, J=7.2 Hz), 3.27-3.30 (2H, m), 3.73(3H, s), 3.98 (3H, s), 6.43 (1H, d, J=5.2 Hz), 6.70 (1H, d, J=3.2 Hz),7.15-7.20 (1H, m), 7.45-7.53 (2H, m), 7.93 (1H, d, J=3.6 Hz), 8.21-8.26(1H, m), 8.35 (1H, d, J=8.8 Hz), 8.48 (1H, s), 8.61 (1H, d, J=5.2 Hz),11.45 (1H, brs)

Example 5216-Methoxycarbamoyl-7-methoxy-4-((1-cyclopropylcarbamoyl)indol-5-yloxy)quinoline

The title compound was obtained from6-methoxycarbamoyl-7-methoxy-4-(indol-5-yloxy)quinoline usingcyclopropylcarbamic acid phenyl ester, by the same procedure as inExample 515.

¹H-NMR (DMSO-d₆) δ (ppm) 0.58-0.65 (2H, m), 0.70-0.77 (2H, m), 2.73-2.82(1H, m), 3.73 (3H, s), 3.98 (3H, s), 6.42 (1H, d, J=5.2 Hz), 6.68 (1H,d, J=3.6 Hz), 7.15-7.20 (1H, m), 7.47-7.52 (2H, m), 7.89 (1H, d, J=3.6Hz), 8.28-8.36 (2H, m), 8.48 (1H, s), 8.61 (1H, d, J=5.2 Hz), 11.44 (1H,brs)

Example 5226-(Pyridin-2-ylcarbamoyl)-7-methoxy-4-(indol-5-yloxy)quinoline

The title compound was obtained from6-carboxy-7-methoxy-4-(indol-5-yloxy)quinoline using 2-aminopyridine, bythe same procedure as in Example 514.

¹H-NMR (DMSO-d₆) δ (ppm) 4.08 (3H, s), 6.39-6.48 (2H, m), 6.97-7.02 (1H,m), 7.15-7.20 (1H, m), 7.43-7.60 (4H, m), 7.83-7.89 (1H, m), 8.25-8.38(2H, m), 8.60-8.80 (2H, m), 10.70 (1H, brs), 11.30 (1H, brs)

Example 5236-(Pyridin-2-ylcarbamoyl)-7-methoxy-4-((1-ethylcarbamoyl)indol-5-yloxy)quinoline

The title compound was obtained from6-(pyridin-2-ylcarbamoyl)-7-methoxy-4-(indol-5-yloxy)quinoline, by thesame procedure as in Example 515.

¹H-NMR (DMSO-d₆) δ (ppm) 1.18 (3H, t, J=7.6 Hz), 3.27-3.30 (2H, m), 4.10(3H, s), 6.46 (1H, d, J=5.2 Hz), 6.71 (1H, d, J=3.6 Hz), 7.15-7.21 (2H,m), 7.53 (1H, d, J=2.8 Hz), 7.60 (1H, s), 7.83-7.89 (1H, m), 7.93 (1H,d, J=3.6 Hz), 8.22-8.38 (4H, m), 8.65 (1H, d, J=5.2 Hz), 8.76 (1H, d,J=5.2 Hz), 10.70 (1H, brs)

Example 5246-Methoxycarbonyl-7-methoxy-4-[1-(2-fluoroethylcarbamoyl)indol-5-yloxy]quinoline

The title compound was obtained from6-methoxycarbonyl-7-methoxy-4-(indol-5-yloxy)quinoline using2-fluoroethylcarbamic acid phenyl ester, in the same manner as Example515.

¹H-NMR (DMSO-d₆) δ (ppm) 3.50-3.68 (2H, m), 3.84 (3H, s), 3.97 (3H, s),4.48-4.70 (2H, m), 6.42 (1H, d, J=5.6 Hz), 6.72 (1H, d, J=3.6 Hz),7.17-7.22 (1H, m), 7.45-7.56 (2H, m), 7.98 (1H, d, J=3.6 Hz), 8.35 (1H,d, J=9.2 Hz), 8.46-8.53 (1H, m), 8.58-8.64 (2H, m)

Example 5256-Carboxy-7-methoxy-4-[1-(2-fluoroethylcarbamoyl)indol-5-yloxy]quinoline

The title compound was obtained from6-methoxycarbonyl-7-methoxy-4-[1-(2-fluoroethylcarbamoyl)indol-5-yloxy]quinolineusing 2-phenylcarbamic acid phenyl ester, by the same procedure as inExample 513.

¹H-NMR (DMSO-d₆) δ (ppm) 3.50-3.70 (2H, m), 3.94 (3H, s), 4.48-4.70 (2H,m), 6.42 (1H, d, J=5.2 Hz), 6.72 (1H, d, J=3.6 Hz), 7.18-7.22 (1H, m),7.42-7.55 (2H, m), 7.98 (1H, d, J=3.6 Hz), 8.35 (1H, d, J=9.2 Hz),8.46-8.52 (1H, m), 8.54-8.64 (2H, m)

Example 5266-Methoxycarbamoyl-7-methoxy-4-[1-(2-fluoroethylcarbamoyl)indol-5-yloxy]quinoline

The title compound was obtained from6-carboxy-7-methoxy-4-[1-(2-fluoroethylcarbamoyl)indol-5-yloxy]quinolineusing methylhydroxylamine hydrochloride, by the same procedure as inExample 514.

¹H-NMR (DMSO-d₆) δ (ppm) 3.53-3.66 (2H, m), 3.73 (3H, s), 3.98 (3H, s),4.50-4.68 (2H, m), 6.43 (1H, d, J=5.2 Hz), 6.73 (1H, d, J=3.6 Hz),7.15-7.21 (1H, m), 7.47-7.54 (2H, m), 7.98 (1H, d, J=3.6 Hz), 8.35 (1H,d, J=8.4 Hz), 8.46-8.53 (2H, m), 8.61 (1H, d, J=5.2 Hz), 11.5 (1H, brs)

Example 5276-Isobutoxycarbamoyl-7-methoxy-4-[1-(2-fluoroethylcarbamoyl)indol-5-yloxy]quinoline

The title compound was obtained from6-carboxy-7-methoxy-4-[1-(2-fluoroethylcarbamoyl)indol-5-yloxy]quinolineusing o-isobutylhydroxylamine hydrochloride, by the same procedure as inExample 514.

¹H-NMR (DMSO-d₆) δ (ppm) 0.93 (6H, d), 1.90-2.00 (1H, m), 3.52-3.67 (2H,m), 3.70 (2H, d, J=6.8 Hz), 3.97 (3H, s), 4.50-4.69 (2H, m), 6.43 (1H,d, J=5.6 Hz), 6.73 (1H, d, J=4.0 Hz), 7.15-7.21 (1H, m), 7.47-7.54 (2H,m), 7.98 (1H, d, J=4.0 Hz), 8.35 (1H, d, J=9.2 Hz), 8.41 (1H, s),8.45-8.55 (1H, m), 8.61 (1H, d, J=5.6 Hz), 11.84 (1H, brs)

Example 528N-[2-Fluoro-4-([6-cyano-7-([(2R)-2-hydroxy-3-(1-pyrrolidino)propyl]oxy)-4-quinolyl]oxy)phenyl]-N′-(2-thiazolyl)urea

The title compound was obtained fromN-(4-{6-cyano-7-[(2R)-oxiran-2-yl]methoxyquinolin-4-yloxy}-2-fluorophenyl)-N′-(thiazol-2-yl)urea,by the method described in Example 495.

¹H-NMR (DMSO-d₆) δ (ppm) 1.60-1.70 (4H, m), 2.40-2.75 (6H, m), 3.95-4.05(1H, m), 4.20 (1H, dd, J=10, 6.0 Hz), 4.31 (1H, dd, J=10, 4 Hz), 5.02(1H, brs), 6.62 (1H, d, J=5.2 Hz), 7.10-7.20 (2H, m), 7.37-7.47 (2H, m),7.62 (1H, s), 8.20-8.26 (1H, m), 8.71-8.76 (2H, m), 9.05 (1H, brs)

Example 529N-[2-Fluoro-4-([6-cyano-7-([(2R)-2-hydroxy-3-(1-piperidino)propyl]oxy)-4-quinolyl]oxy)phenyl]-N′-(2-thiazolyl)urea

The title compound was obtained fromN-(4-{6-cyano-7-[(2R)-oxiran-2-yl]methoxyquinolin-4-yloxy}-2-fluorophenyl)-N′-thiazol-2-yl-urea,by the method described in Example 496.

¹H-NMR (DMSO-d₆) δ (ppm) 1.30-1.55 (6H, m), 2.32-2.55 (6H, m), 3.97-4.16(1H, m), 4.20 (1H, dd, J=10, 6 Hz), 4.30 (1H, dd, J=10, 4.0 Hz), 4.44(1H, brs), 6.62 (1H, d, J=5.2 Hz), 7.11-7.21 (2H, m), 7.37-7.47 (2H, m),7.64 (1H, s), 8.20-8.27 (1H, m), 8.72-8.76 (2H, m)

Example 530N-[2-Fluoro-4-([6-cyano-7-([(2R)-2-hydroxy-3-(1-pyrrolidino)propyl]oxy)-4-quinolyl]oxy)phenyl]-N′-cyclopropylurea

The title compound was obtained fromN-(2-fluoro-4-[(6-cyano-7-[(2R)-(oxiran-2-yl)methoxy]-4-quinolyl)oxy]phenyl)-N′-cyclopropylurea,by the method described in Example 492.

¹H-NMR (DMSO-d₆) δ (ppm) 0.37-0.44 (2H, m), 0.62-0.69 (2H, m), 1.63-1.75(4H, m), 2.45-2.60 (6H, m), 2.65-2.77 (1H, m), 3.98-4.08 (1H, m), 4.22(1H, dd, J=10, 5.2 Hz), 4.31 (1H, dd, J=10, 3.6 Hz), 5.04 (1H, brs),6.59 (1H, d, J=5.6 Hz), 6.82-6.85 (1H, m), 7.08-7.13 (1H, m), 7.32-7.38(1H, m), 7.63 (1H, s), 8.20-8.28 (2H, m), 8.72-8.76 (2H, m)

The starting material was synthesized by the following 2 steps.

Production Example 530-1[2-Fluoro-4-([6-cyano-7-([(2R)-(oxiran-2-yl]methoxy)-4-quinolyl]oxy)phenyl]carbamicacid phenyl ester

This was synthesized from4-(4-amino-3-fluoro-phenoxy)-7-[(2R)-oxiran-2-yl]methoxyquinoline-6-carbonitrile,by the method described in Production Example 141-1.

¹H-NMR(CDCl₃) δ (ppm) 2.90-3.01 (2H, m), 3.44-3.55 (1H, m), 4.21-4.28(1H, m), 4.47-4.54 (1H, m), 6.53 (1H, d, J=5.2 Hz), 7.00-7.06 (2H, m),7.19-7.30 (4H, m), 7.40-7.46 (2H, m), 7.48-7.53 (1H, m), 8.27 (1H, brs),8.65-8.73 (2H, m)

Production Example 530-2N-(2-Fluoro-4-[(6-cyano-7-[(2R)-(oxiran-2-yl)methoxy]-4-quinolyl)oxy]phenyl)-N′-cyclopropylurea

Cyclopropylamine (0.04 ml) was added to dimethylsulfoxide (3 ml), andthen[2-fluoro-4-([6-cyano-7-([(2R)-oxiran-2-yl]methoxy)-4-quinolyl]oxy)phenyl]carbamicacid phenyl ester (212 mg) was dissolved therein and the solution wasstirred for 10 minutes. Water and ethyl acetate were added to thereaction solution, and the precipitated crystals were filtered out toobtain the title compound (150 mg).

¹H-NMR (DMSO-d₆) δ (ppm) 0.37-0.44 (2H, m), 0.61-0.69 (2H, m), 2.50-2.60(1H, m), 2.78-2.79 (2H, m), 3.45-3.50 (1H, m), 4.20 (1H, dd, J=12, 6.0Hz), 4.73 (1H, dd, J=12, 2.4 Hz), 6.59 (1H, d, J=5.6 Hz), 6.82-6.85 (1H,m), 7.08-7.13 (1H, m), 7.32-7.38 (1H, m), 7.63 (1H, s), 8.20-8.28 (2H,m), 8.72-8.78 (2H, m)

Example 531N-[2-Fluoro-4-([6-cyano-7-([(2R)-2-hydroxy-3-(1-piperidino)propyl]oxy)-4-quinolyl]oxy)phenyl]-N′-cyclopropylurea

The title compound was obtained fromN-(2-fluoro-4-[(6-cyano-7-[(2R)-(oxiran-2-yl)methoxy]-4-quinolyl)oxy]phenyl)-N′-cyclopropylurea,by the method described in Example 496.

¹H-NMR (DMSO-d₆) δ (ppm) 0.38-0.44 (2H, m), 0.62-0.69 (2H, m), 1.33-1.54(6H, m), 2.30-2.70 (7H, m), 4.00-4.09 (1H, m), 4.21 (1H, dd, J=10.4, 5.6Hz), 4.32 (1H, dd, J=10.4, 3.2 Hz), 4.95 (1H, d, J=4.4 Hz), 6.59 (1H, d,J=5.6 Hz), 6.83-6.85 (1H, m), 7.08-7.13 (1H, m), 7.32-7.38 (1H, m), 7.64(1H, s), 8.20-8.28 (2H, m), 8.72-8.78 (2H, m)

Example 532N-[2-Fluoro-4-([6-cyano-7-([3-(1-piperidino)propyl]oxy)-4-quinolyl]oxy)phenyl]-N′-(2-thiazolyl)urea

The title compound was obtained from2-fluoro-4-([6-cyano-7-([3-(1-piperidino)propyl]oxy)-4-quinolyl]oxy)phenylamine,by the method described in Example 495.

¹H-NMR (DMSO-d₆) δ (ppm) 1.30-1.53 (6H, m), 1.92-2.00 (2H, m), 2.30-2.50(6H, m), 4.28-4.35 (2H, m), 6.62 (1H, d, J=5.6 Hz), 7.12-7.20 (2H, m),7.36-7.47 (2H, m), 7.60 (1H, s), 8.20-8.28 (1H, m), 8.72-8.77 (2H, m).

The starting material was synthesized in the following manner.

Production Example 532-12-Fluoro-4-([6-cyano-7-([3-(1-piperidino)propyl]oxy)-4-quinolyl]oxy)phenylamine

After adding dimethylformamide (4 ml),1-(3-chloropropylpiperidine)hydrochloride (268 mg) and potassiumcarbonate (374 mg) to4-(4-amino-3-fluorophenoxy)-6-cyano-7-hydroxyquinoline (200 mg), themixture was heated at 60° C. for 8 hours. Water was added to thereaction solution, extraction was performed with ethyl acetate and theorganic layer was washed with water and saturated brine in that orderand then dried over anhydrous sodium sulfate, and the solvent wasdistilled off under reduced pressure. The obtained crude product waspurified by silica gel column chromatography (ethyl acetate) to obtainthe title compound (80 mg) as light yellow crystals.

¹H-NMR(CDCl₃) δ (ppm) 1.38-1.64 (6H, m), 2.07-2.18 (2H, m), 2.37-2.48(6H, m), 3.79 (2H, brs), 4.24-4.34 (2H, m), 6.47 (1H, d, J=5.6 Hz),6.77-6.92 (3H, m), 7.46 (1H, s), 8.63-8.67 (2H, m)

Example 533N-[2-Fluoro-4-([6-cyano-7-([3-(1-pyrrolidino)propyl]oxy)-4-quinolyl]oxy)phenyl]-N′-(2-thiazolyl)urea

The title compound was obtained from2-fluoro-4-([6-cyano-7-([3-(1-pyrrolidino)propyl]oxy)-4-quinolyl]oxy)phenylamine,by the method described in Example 495.

¹H-NMR (DMSO-d₆) δ (ppm) 1.65-1.72 (4H, m), 1.94-2.02 (2H, m), 2.40-2.50(4H, m), 2.56-2.62 (2H, m), 4.30-4.36 (2H, m), 6.63 (1H, d, J=5.6 Hz),7.13-7.20 (2H, m), 7.37-7.47 (2H, m), 7.60 (1H, s), 8.20-8.27 (1H, m),8.72-8.76 (2H, m)

The starting material was synthesized in the following manner.

Production Example 533-12-Fluoro-4-([6-cyano-7-([3-(1-pyrrolidino)propyl]oxy)-4-quinolyl]oxy)phenylamine

After adding dimethylformamide (4 ml),1-(3-chloropropylpyrrolidine)hydrochloride (376 mg) and potassiumcarbonate (553 mg) to4-(4-amino-3-fluorophenoxy)-6-cyano-7-hydroxyquinoline (300 mg), themixture was heated at 60° C. for 8 hours. Water was added to thereaction solution, extraction was performed with ethyl acetate and theorganic layer was washed with water and saturated brine in that orderand then dried over anhydrous sodium sulfate, and the solvent wasdistilled off under reduced pressure. The obtained crude product waspurified by silica gel column chromatography (ethyl acetate) to obtainthe title compound (200 mg) as light yellow crystals.

¹H-NMR (DMSO-d₆) δ (ppm) δ (ppm) 1.62-1.72 (4H, m), 1.93-2.03 (2H, m),2.40-2.49 (4H, m), 2.55-2.61 (2H, m), 4.28-4.35 (2H, m), 5.22-5.25 (2H,m), 6.51 (1H, d, J=4.8 Hz), 6.82-6.90 (2H, m), 7.06-7.12 (1H, m) 7.56(1H, s), 8.68-8.72 (2H, m)

Example 534N-(2-Chloro-5-((6-cyano-7-(2-(1-pyrrolidino)ethoxy)-4-quinolyl)oxy)phenyl)-N′-phenylurea

The title compound (19.8 mg, 0.038 mmol, 34.5%) was obtained as whitecrystals from4-(3-amino-4-chlorophenoxy)-6-cyano-7-(2-(1-pyrrolidino)ethoxy)quinoline(44.5 mg, 0.109 mmol) and phenyl isocyanate, by the same procedure as inExample 11.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.69 (4H, m), 2.59 (4H, m), 2.91 (2H,t, J=5.6 Hz), 4.38 (2H, t, J=5.6 Hz), 6.66 (1H, d, J=5.2 Hz), 6.97-7.01(2H, m), 7.24-7.28 (2H, m), 7.41 (2H, d, J=7.2 Hz), 7.60-7.63 (2H, m),8.20 (1H, m), 8.51 (1H, s), 8.74-8.76 (2H, m), 9.53 (1H, d, J=4.4 Hz).

The starting materials were synthesized in the following manner.

Production Example 534-17-(Benzyloxy)-4-(4-chloro-3-nitrophenoxy)-6-cyanoquinoline

The title compound (4.794 g, 11.10 mmol, 59.9%) was obtained as lightbrown crystals from 7-(benzyloxy)-4-chloro-6-cyanoquinoline (5.462 g,18.53 mmol) and 4-chloro-3-nitrophenol, by the same procedure as inProduction Example 11.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 5.74 (2H, s), 6.57 (1H, d, J=5.2 Hz),7.34-7.55 (6H, m), 7.58 (1H, s), 7.70 (1H, d, J=8.8 Hz), 7.76 (1H, d,J=2.8 Hz), 8.64 (1H, s), 8.76 (1H, d, J=5.2 Hz).

Production Example 534-24-(4-Chloro-3-nitrophenoxy)-6-cyano-7-hydroxyquinoline

The title compound (743 mg, 2.17 mmol, 93.9%) was obtained as lightyellow crystals from7-(benzyloxy)-4-(4-chloro-3-nitrophenoxy)-6-cyanoquinoline (1.00 g, 2.32mmol), by the same procedure as in Example 83.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 6.73 (1H, d, J=5.2 Hz), 7.45 (1H, s),7.69 (1H, dd, J=2.8, 8.8 Hz), 7.91 (1H, d, J=8.8 Hz), 8.14 (1H, d, J=2.8Hz), 8.67 (1H, s), 8.71 (1H, d, J=5.2 Hz), 11.71 (1H, br).

Production Example 534-34-(3-Amino-4-chlorophenoxy)-6-cyano-7-hydroxyquinoline

The title compound (464 mg, 1.49 mmol, 68.5%) was obtained as lightyellow crystals from4-(4-chloro-3-nitrophenoxy)-6-cyano-7-hydroxyquinoline (743 mg, 2.17mmol), by the same procedure as in Production Example 6.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 5.62-5.65 (2H, m), 6.43 (1H, dd,J=2.8, 8.8 Hz), 6.54 (1H, d, J=5.2 Hz), 6.63 (1H, d, J=2.8 Hz), 7.30(1H, d, J=8.8 Hz), 7.41 (1H, s), 8.62 (1H, s), 8.65 (1H, d, J=5.2 Hz).

Production Example 534-44-(3-Amino-4-chlorophenoxy)-6-cyano-7-(2-(1-pyrrolidino)ethoxy)quinoline

The title compound (143 mg, 0.350 mmol, 54.5%) was obtained as whitecrystals from 4-(3-amino-4-chlorophenoxy)-6-cyano-7-hydroxyquinoline(200 mg, 0.642 mmol) and 1-(2-chloroethyl)pyrrolidine hydrochloride, bythe same procedure as in Example 7.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.84 (4H, m), 2.74 (4H, m), 3.08 (2H,t, J=5.6 Hz), 4.20-4.24 (2H, m), 4.37 (2H, t, J=5.6 Hz), 6.50 (1H, dd,J=2.8, 8.8 Hz), 6.54 (1H, d, J=5.2 Hz), 6.59 (1H, d, J=2.8 Hz), 7.33(1H, d, J=8.8 Hz), 7.46 (1H, s), 8.64 (1H, s), 8.68 (1H, d, J=5.2 Hz).

Example 535N-(2-Chloro-5-((6-cyano-7-(2-(1-pyrrolidino)ethoxy)-4-quinolyl)oxy)phenyl)-N′-(1,3-thiazol-2-yl)urea

The title compound (5.7 mg, 0.011 mmol, 9.35%) was obtained as whitecrystals from4-(3-amino-4-chlorophenoxy)-6-cyano-7-(2-(1-pyrrolidino)ethoxy)quinoline(46.6 mg, 0.114 mmol) and phenyl N-(1,3-thiazol-2-yl)carbamate, by thesame procedure as in Example 131.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.69 (4H, m), 2.61 (4H, m), 2.93 (2H,m), 4.39 (2H, m), 6.65 (1H, d, J=5.2 Hz), 7.06 (1H, dd, J=2.8, 8.8 Hz),7.13-7.14 (2H, m), 7.38-7.40 (2H, m), 7.63 (1H, s), 7.66 (1H, d, J=8.8Hz), 8.19 (1H, d, J=3.2 Hz), 8.75 (1H, d, J=5.2 Hz), 8.77 (1H, s).

Example 536N-(2-Chloro-5-((6-cyano-7-(2-(1-pyrrolidino)ethoxy)-4-quinolyl)oxy)phenyl)-N′-cyclopropylurea

After dissolving4-(3-amino-4-chlorophenoxy)-6-cyano-7-(2-(1-pyrrolidino)ethoxy)quinoline(47.9 mg, 0.117 mmol) in dimethylformamide (1 ml) in a nitrogenatmosphere, pyridine (0.019 ml, 0.234 mmol) and phenyl chloroformate(0.030 ml, 0.234 mmol) were added dropwise at room temperature and themixture was stirred for 1 hour. Cyclopropylamine (0.1 ml) was addeddropwise, and the mixture was further stirred overnight. The reactionsolution was distributed between ethyl acetate and water, washed withsaturated brine and dried over anhydrous sodium sulfate. Afterdistilling off the solvent, the crystals precipitated from ethyl acetatewere filtered out and blow-dried to obtain the title compound (12.6 mg,0.026 mmol, 21.9%) as light brown crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.39 (2H, m), 0.63 (2H, m), 1.70 (4H,m), 2.49-2.53 (1H, m), 2.60 (4H, m), 2.91 (2H, m), 4.40 (2H, m), 6.64(1H, d, J=5.2 Hz), 6.93 (1H, dd, J=2.8, 8.8 Hz), 7.33 (1H, d, J=2.8 Hz),7.57 (1H, d, J=8.8 Hz), 7.64 (1H, s), 8.09 (1H, s), 8.19 (1H, d, J=2.8Hz), 8.75-8.77 (2H, m).

Example 537N-(2-Chloro-5-((6-cyano-7-((2R)-2-hydroxy-3-(1-pyrrolidino)propoxy)-4-quinolyl)oxy)phenyl)-N′-cyclopropylurea

The title compound (20.7 mg, 0.040 mmol, 20.7%) was obtained as a whitepowder from phenylN-(2-chloro-5-((6-cyano-7-((2R)-2-hydroxy-3-(1-pyrrolidino)propoxy-4-quinolyl)oxy)phenyl)carbamate)(107 mg, 0.191 mmol) and cyclopropylamine, by the same procedure as inExample 11.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.40 (2H, m), 0.65 (2H, m), 1.69 (4H,m), 2.49-2.68 (6H, m), 2.72 (1H, m), 4.03 (1H, m), 4.23 (1H, dd, J=5.6,10.4 Hz), 4.33 (1H, dd, J=4.4, 10.4 Hz), 5.03 (1H, m), 6.64 (1H, d,J=5.2 Hz), 6.94 (1H, dd, J=2.8, 8.4 Hz), 7.33 (1H, m), 7.56-7.93 (2H,m), 8.10 (1H, s), 8.20 (1H, d, J=2.8 Hz), 8.71-8.77 (2H, m).

The starting materials were synthesized in the following manner.

Production Example 537-14-(3-Amino-4-chlorophenoxy)-6-cyano-7-((2R)oxiran-2-yl)methoxyquinoline

The title compound (201 mg, 0.547 mmol, 64.6%) was obtained as lightyellow crystals from4-(3-amino-4-chlorophenoxy)-6-cyano-7-hydroxyquinoline (264 mg, 0.847mmol) and (2R)oxiran-2-ylmethyl 4-methyl-1-benzenesulfonate, by the sameprocedure as in Example 7.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 2.93 (1H, dd, J=2.4, 4.8 Hz), 2.98 (1H,dd, J=4.0, 4.8 Hz), 3.50 (1H, m), 4.21-4.24 (3H, m), 4.50 (1H, dd,J=3.2, 11.2 Hz), 6.50 (1H, dd, J=2.8, 8.8 Hz), 6.56 (1H, d, J=5.2 Hz),6.59 (1H, d, J=2.8 Hz), 7.33 (1H, d, J=8.8 Hz), 7.48 (1H, s), 8.67 (1H,s), 8.69 (1H, d, J=5.2 Hz).

Production Example 537-24-(3-Amino-4-chlorophenoxy)-6-cyano-7-(((2R)-2-hydroxy-3-(1-pyrrolidino)propyl)oxy)quinoline

After dissolving4-(3-amino-4-chlorophenoxy)-6-cyano-7-((2R)oxiran-2-yl)methoxyquinoline)(201 mg, 0.547 mmol) in tetrahydrofuran (5.0 ml) under a nitrogenatmosphere, pyrrolidine (0.456 ml) was added and the mixture was stirredat room temperature overnight. The reaction solution was concentratedunder reduced pressure, the residue was subjected to silica gel columnchromatography (eluent—ethyl acetate), the fraction containing thetarget substance was concentrated, suspended in ethyl acetate anddiluted with hexane, and the crystals were filtered out and blow-driedto obtain the title compound (235 mg, 0.535 mmol, 98.0%) as light yellowcrystals.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.82 (4H, m), 2.59 (2H, m), 2.65 (1H,dd, J=4.0, 12.0 Hz), 2.74 (2H, m), 2.94 (1H, dd, J=5.2, 12.0 Hz),4.19-4.27 (5H, m), 6.50 (1H, dd, J=2.8, 8.8 Hz), 6.55 (1H, d, J=5.2 Hz),6.59 (1H, d, J=2.8 Hz), 7.33 (1H, d, J=8.8 Hz), 7.50 (1H, s), 8.65 (1H,s), 8.68 (1H, d, J=5.2 Hz).

Production Example 537-3 PhenylN-(2-chloro-5-((6-cyano-7-((2R)-2-hydroxy-3-(1-pyrrolidino)propoxy-4-quinolyl)oxy)phenyl)carbamate

The title compound (107 mg, 0.191 mmol, 35.7%) was obtained as whitecrystals from4-(3-amino-4-chlorophenoxy)-6-cyano-7-(((2R)-2-hydroxy-3-(1-pyrrolidino)propyl)oxy)quinoline(235 mg, 0.535 mmol), by the same procedure as in Production Example 17.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 2.20 (4H, m), 3.39-3.48 (5H, m), 4.11(1H, m), 4.25 (1H, m), 4.44 (1H, dd, J=4.8, 9.2 Hz), 4.67 (1H, m), 6.50(1H, m), 6.57-6.60 (2H, m), 6.91 (1H, m), 7.17-7.49 (6H, m), 8.17 (1H,s), 8.66 (1H, d, J=5.2 Hz), 8.71 (1H, d, J=5.6 Hz).

Example 538N6-Methyl-4-(4-chloro-3-(((4-fluoroanilino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (77.6 mg, 0.157 mmol, 77.9%) was obtained as whitecrystals fromN6-methyl-4-(3-amino-4-chlorophenoxy)-7-methoxy-6-quinolinecarboxamide(72 mg, 0.2 mmol) and 4-fluorophenyl isocyanate, by the same procedureas in Example 11.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.82 (3H, d, J=4.4 Hz), 4.01 (3H, s),6.62 (1H, d, J=5.2 Hz), 6.96 (1H, dd, J=2.8, 8.8 Hz), 7.10 (2H, m), 7.40(2H, m), 7.51 (1H, s), 7.60 (1H, d, J=8.8 Hz), 8.15 (1H, d, J=2.8 Hz),8.35 (1H, d, J=4.4 Hz), 8.47 (1H, s), 8.54 (1H, s), 8.68 (1H, d, J=5.2Hz), 9.56 (1H, s).

The starting materials were synthesized in the following manner.

Production Example 538-1 Methyl4-(4-chloro-3-nitrophenoxy)-7-methoxy-6-quinoline carboxylate

The title compound (2.114 g, 5.44 mmol, 54.4%) was obtained as lightyellow crystals from methyl 4-chloro-7-methoxy-6-quinoline carboxylate(2.517 g, 10.0 mmol) and 4-chloro-3-nitrophenol, by the same procedureas in Production Example 11.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 3.97 (3H, s), 4.06 (3H, s), 6.54 (1H,d, J=5.2 Hz), 7.38 (1H, dd, J=2.8, 8.8 Hz), 7.53 (1H, s), 7.66 (1H, d,J=8.8 Hz), 7.75 (1H, d, J=2.8 Hz), 8.70 (1H, s), 8.73 (1H, d, J=8.8 Hz).

Production Example 538-24-(4-Chloro-3-nitrophenoxy)-7-methoxy-6-quinolinecarboxylic acid

After adding methanol (30 ml) and 2N aqueous sodium hydroxide (10 ml) tomethyl 4-(4-chloro-3-nitrophenoxy)-7-methoxy-6-quinolinecarboxylate(1.00 g, 2.57 mmol), the mixture was stirred at 60° C. for 1 hour. Thereaction solution was allowed to cool to room temperature, 2Nhydrochloric acid was added for neutralization, the methanol wasdistilled off, and the precipitated light brown crystals were filteredout, thoroughly washed with water and dried at 70° C. to obtain thetitle compound (897 mg, 2.39 mmol, 93.1%).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.97 (3H, s), 6.76 (1H, d, J=5.2 Hz),7.53 (1H, s), 7.70 (1H, dd, J=2.8, 8.8 Hz), 7.91 (1H, d, J=8.8 Hz), 8.16(1H, d, J=2.8 Hz), 8.49 (1H, s), 8.73 (1H, d, J=5.2 Hz), 13.13 (1H, br).

Production Example 538-3N6-Methyl-4-(4-chloro-3-nitrophenoxy)-7-methoxy-6-quinolinecarboxamide

After dissolving4-(4-chloro-3-nitrophenoxy)-7-methoxy-6-quinolinecarboxylic acid (897mg, 2.39 mmol) in dimethylformamide (10 ml) under a nitrogen atmosphere,a 40% methylamine-methanol solution (2.0 ml), triethylamine (1.0 ml) and(1H-1,2,3-benzotriazol-1-yloxy)(tri(dimethylamino))phosphoniumhexafluorophosphate (1.27 g, 2.87 mmol) were added in that order at roomtemperature and the mixture was stirred for 4 hours. The reactionsolution was distributed between ethyl acetate and water, and theorganic layer was washed with water and saturated brine and dried overanhydrous sodium sulfate. The solvent was distilled off, the residue wassuspended in ethyl acetate and diluted with hexane, and the crystalswere filtered out and blow-dried to obtain the title compound (928 mg,quantitative) as white crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.82 (3H, d, J=4.4 Hz), 4.01 (3H, s),6.77 (1H, d, J=5.2 Hz), 7.54 (1H, s), 7.68 (1H, dd, J=2.8, 8.8 Hz), 7.90(1H, d, J=8.8 Hz), 8.13 (1H, d, J=2.8 Hz), 8.35 (1H, d, J=4.4 Hz), 8.53(1H, s), 8.72 (1H, d, J=5.2 Hz).

Production Example 538-4N6-Methyl-4-(3-amino-4-chlorophenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (614 mg, 1.72 mmol, 71.7%) was obtained as light graycrystals fromN6-methyl-4-(4-chloro-3-nitrophenoxy)-7-methoxy-6-quinolinecarboxamide(928 mg, 2.39 mmol), by the same procedure as in Production Example 6.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 3.08 (3H, d, J=5.2 Hz), 4.12 (3H, s),4.17-4.21 (2H, m), 6.49-6.54 (2H, m), 6.59 (1H, d, J=2.8 Hz), 7.30 (1H,d, J=8.8 Hz), 7.51 (1H, s), 7.86 (1H, br), 8.64 (1H, d, J=5.2 Hz), 9.23(1H, s).

Example 539N6-Methyl-4-(4-chloro-3-(((1,3-thiazol-2-ylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (170.4 mg, 0.352 mmol, 88.0%) was obtained as whitecrystals fromN6-methyl-4-(3-amino-4-chlorophenoxy)-7-methoxy-6-quinolinecarboxamide(143 mg, 0.4 mmol) and phenyl N-(1,3-thiazol-2-yl)carbamate, by the sameprocedure as in Example 131.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.82 (3H, d, J=4.8 Hz), 4.01 (3H, s),6.62 (1H, d, J=5.2 Hz), 7.03 (1H, dd, J=2.8, 8.8 Hz), 7.13 (1H, d, J=3.6Hz), 7.39 (1H, d, J=3.6 Hz), 7.52 (1H, s), 7.64 (1H, d, J=8.8 Hz), 8.16(1H, d, J=2.8 Hz), 8.35 (1H, d, J=4.8 Hz), 8.55 (1H, s), 8.68 (1H, d,J=5.2 Hz), 11.30 (1H, br).

Example 540N6-Methyl-4-(4-chloro-3-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

After dissolvingN6-methyl-4-(3-amino-4-chlorophenoxy)-7-methoxy-6-quinolinecarboxamide(179 mg, 0.50 mmol) in dimethylformamide (2 ml) under a nitrogenatmosphere, pyridine (0.061 ml, 0.75 mmol) and phenyl chloroformate(0.094 ml, 0.75 mmol) were added dropwise at room temperature and themixture was stirred for 1 hour. Cyclopropylamine (0.2 ml) was addeddropwise and the mixture was further stirred overnight. The reactionsolution was distributed between ethyl acetate and water, washed withsaturated brine and dried over anhydrous sodium sulfate. Afterdistilling off the solvent, the crystals precipitated from ethyl acetatewere filtered out and blow-dried to obtain the title compound (163.9 mg,0.372 mmol, 74.3%) as white crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.39 (2H, m), 0.62 (2H, m), 2.49-2.53(1H, m), 2.83 (3H, d, J=4.8 Hz), 4.02 (3H, s), 6.60 (1H, d, J=5.2 Hz),6.90 (1H, dd, J=3.2, 8.8 Hz), 7.32 (1H, d, J=2.8 Hz), 7.52-7.56 (2H, m),8.07 (1H, s), 8.16 (1H, d, J=3.2 Hz), 8.37 (1H, d, J=4.8 Hz), 8.54 (1H,s), 8.67 (1H, d, J=5.2 Hz).

Example 541N6-Methyl-4-(4-chloro-3-(((methylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (71.9 mg, 0.173 mmol, 57.4%) was obtained as whitecrystals fromN6-methyl-4-(3-amino-4-chlorophenoxy)-7-methoxy-6-quinolinecarboxamide(108 mg, 0.30 mmol), by the same procedure as in Example 540.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.60 (3H, d, J=4.4 Hz), 2.81 (3H, d,J=4.8 Hz), 4.00 (3H, s), 6.59 (1H, d, J=5.2 Hz), 6.87 (1H, dd, J=2.8,8.4 Hz), 7.14 (1H, t, J=7.6 Hz), 7.50-7.54 (2H, m), 8.13 (1H, d, J=2.8Hz), 8.19 (1H, s), 8.35 (1H, d, J=4.4 Hz), 8.53 (1H, s), 8.67 (1H, d,J=5.2 Hz).

Example 542N6-Methyl-4-(4-chloro-3-(((ethylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (90.6 mg, 0.211 mmol, 70.6%) was obtained as whitecrystals fromN6-methyl-4-(3-amino-4-chlorophenoxy)-7-methoxy-6-quinolinecarboxamide(107 mg, 0.30 mmol), by the same procedure as in Example 540.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.02 (3H, t, J=7.2 Hz), 2.81 (3H, t,J=4.4 Hz), 3.06 (2H, m), 4.00 (3H, s), 6.58 (1H, d, J=5.2 Hz), 6.87 (1H,dd, J=3.2, 8.8 Hz), 7.13 (1H, m), 7.50-7.54 (2H, m), 8.14-8.15 (2H, m),8.35 (1H, d, J=4.4 Hz), 8.53 (1H, s), 8.67 (1H, d, J=5.2 Hz).

Example 543N-(2-Chloro-4-(6-cyano-7-(((2R)oxiran-2-ylmethoxy)-4-quinolyl)oxy)phenyl)-N′-cyclopropylurea

The title compound (663 mg, 1.47 mmol, 66.5%) was obtained as lightyellow crystals fromN-(4-(6-cyano-7-hydroxy-4-quinolyl)oxy-2-chlorophenyl)-N′-cyclopropylurea(873 mg, 2.21 mmol) and (2R)oxiran-2-ylmethyl4-methyl-1-benzenesulfonate, by the same procedure as in Example 7.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.42 (2H, m), 0.65 (2H, m), 2.56 (1H,m), 2.83 (1H, m), 2.93 (1H, m), 3.48 (1H, m), 4.18 (1H, dd, J=6.4, 12.0Hz), 4.72 (1H, m), 6.61 (1H, d, J=5.2 Hz), 7.20 (1H, d, J=2.8 Hz), 7.27(1H, dd, J=2.4, 9.2 Hz), 7.51 (1H, d, J=2.8 Hz), 7.65 (1H, s), 8.00 (1H,s), 8.29 (1H, dd, J=4.0, 9.2 Hz), 8.75 (1H, d, J=5.2 Hz), 8.78 (1H, s).

Example 544N-(2-Chloro-4-((6-cyano-7-(((2R)-2-hydroxy-3-(1-piperidino)propyl)oxy)-4-quinolyl)oxy)phenyl)-N′-cyclopropylurea

After adding tetrahydrofuran (2.5 ml) and piperidine (0.25 ml) toN-(2-chloro-4-(6-cyano-7-(((2R)oxiran-2-ylmethoxy)-4-quinolyl)oxy)phenyl-N′-cyclopropylurea(113 mg, 0.25 mmol), the mixture was stirred overnight at roomtemperature. The reaction solution was concentrated under reducedpressure, the residue was subjected to silica gel column chromatography(eluent—ethyl acetate), the fraction containing the target substance wasconcentrated, suspended in ethyl acetate and diluted with hexane, andthe crystals were filtered out and blow-dried to obtain the titlecompound (57.7 mg, 0.108 mmol, 43.1%) as white crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.42 (2H, m), 0.65 (2H, m), 1.35 (2H,m), 1.48 (4H, m), 2.34-2.51 (6H, m), 2.56 (1H, m), 4.02 (1H, m), 4.19(1H, dd, J=6.0, 10.4 Hz), 4.29 (1H, dd, J=3.6, 10.4 Hz), 4.93 (1H, d,J=4.0 Hz), 6.57 (1H, d, J=5.2 Hz), 7.19 (1H, d, J=2.8 Hz), 7.25 (1H, dd,J=2.8, 8.8 Hz), 7.50 (1H, d, J=2.8 Hz), 7.62 (1H, s), 7.98 (1H, s), 8.27(1H, d, J=8.8 Hz), 8.71-8.73 (2H, m).

Example 545N6-Methyl-4-(4-(((4-fluoroanilino)carbonyl)(methyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (89.4 mg, 0.188 mmol, 75.6%) was obtained as whitecrystals from4-(4-(((4-fluoroanilino)carbonyl)(methyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid (115 mg, 0.25 mmol) and a 40% methylamine-methanol solution, by thesame procedure as in Example 435.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.83 (3H, d, J=4.8 Hz), 3.28 (3H, s),4.01 (3H, s), 6.65 (1H, d, J=5.2 Hz), 7.08 (2H, m), 7.32 (2H, m),7.42-7.48 (4H, m), 7.51 (1H, s), 8.23 (1H, s), 8.35 (1H, d, J=4.8 Hz),8.60 (1H, s), 8.69 (1H, d, J=5.2 Hz).

Example 546N6-Ethyl-4-(4-(((4-fluoroanilino)carbonyl)(methyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (87.0 mg, 0.178 mmol, 71.5%) was obtained as whitecrystals from4-(4-(((4-fluoroanilino)carbonyl)(methyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid (115 mg, 0.25 mmol) and a 2.0 M ethylamine-tetrahydrofuransolution, by the same procedure as in Example 435.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.13 (3H, t, J=7.2 Hz), 3.28 (3H, s),3.28-3.36 (2H, m), 4.01 (3H, s), 6.64 (1H, d, J=5.2 Hz), 7.06 (2H, m),7.31 (2H, m), 7.42-7.48 (4H, m), 7.51 (1H, s), 8.23 (1H, s), 8.39 (1H,t, J=5.2 Hz), 8.55 (1H, s), 8.68 (1H, d, J=5.2 Hz).

Example 547N6-(2-(1-Pyrrolidino)ethyl)-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (42.9 mg, 0.082 mmol, 81.9%) was obtained as whitecrystals from4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid (43 mg, 0.10 mmol) and 1-(2-aminoethyl)pyrrolidine, by the sameprocedure as in Example 438.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.41 (2H, m), 0.65 (2H, m), 1.70 (4H,m), 2.48-2.61 (7H, m), 3.43 (2H, m), 4.01 (3H, s), 6.52 (1H, d, J=5.2Hz), 7.18 (1H, s), 7.22 (1H, dd, J=2.4, 8.8 Hz), 7.47 (1H, d, J=2.4 Hz),7.51 (1H, s), 7.97 (1H, s), 8.26 (1H, d, J=8.8 Hz), 8.50 (1H, m), 8.64(1H, s), 8.65 (1H, d, J=5.2 Hz).

Example 548N6-(2-(1-Piperidino)ethyl)-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (44.6 mg, 0.083 mmol, 82.9%) was obtained as whitecrystals from4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid (43 mg, 0.10 mmol) and 1-(2-aminoethyl)piperidine, by the sameprocedure as in Example 438.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.41 (2H, m), 0.65 (2H, m), 1.39 (2H,m), 1.51 (4H, m), 2.39 (4H, m), 2.43-2.49 (2H, m), 2.56 (1H, m), 3.39(2H, m), 4.05 (3H, s), 6.52 (1H, d, J=5.2 Hz), 7.18 (1H, s), 7.23 (1H,dd, J=2.8, 8.8 Hz), 7.48 (1H, d, J=2.8 Hz), 7.53 (1H, s), 7.96 (1H, s),8.26 (1H, d, J=8.8 Hz), 8.48 (1H, m), 8.66 (1H, d, J=5.2 Hz), 8.70 (1H,s).

Example 549N6-(2-Propyl)-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (15.2 mg, 0.032 mmol, 32.4%) was obtained as whitecrystals from4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid (43 mg, 0.10 mmol) and 2-propylamine, by the same procedure as inExample 438.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.41 (2H, m), 0.65 (2H, m), 1.17 (6H,d, J=6.8 Hz), 2.56 (1H, m), 3.99 (3H, s), 4.08 (1H, m), 6.51 (1H, d,J=5.2 Hz), 7.19 (1H, s), 7.22 (1H, dd, J=2.8, 8.8 Hz), 7.46 (1H, d,J=2.8 Hz), 7.49 (1H, s), 7.97 (1H, s), 8.15 (1H, d, J=8.0 Hz), 8.26 (1H,d, J=8.8 Hz), 8.43 (1H, s), 8.64 (1H, d, J=5.2 Hz).

Example 550N6-Cyclopentyl-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (34.3 mg, 0.069 mmol, 69.3%) was obtained as whitecrystals from4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid (43 mg, 0.10 mmol) and cyclopentylamine, by the same procedure asin Example 438.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.41 (2H, m), 0.65 (2H, m), 1.53 (4H,m), 1.67 (2H, m), 1.89 (2H, m), 2.56 (1H, m), 4.00 (3H, s), 4.23 (1H,m), 6.51 (1H, d, J=5.2 Hz), 7.18 (1H, s), 7.22 (1H, dd, J=2.8, 8.8 Hz),7.46 (1H, d, J=2.8 Hz), 7.48 (1H, s), 7.97 (1H, s), 8.23-8.27 (2H, m),8.41 (1H, s), 8.64 (1H, d, J=5.2 Hz).

Example 551 N-(4-(6-Aminopyrimidin-4-yloxy)phenyl)-N′-phenylurea

6-(4-Aminophenoxy)pyrimidin-4-ylamine (88.9 mg, 0.440 mmol) and phenylisocyanate (52.4 mg, 0.440 mmol) were stirred together for 3 hours indimethylformamide (2 ml) at room temperature. The reaction solution wasdistributed between ethyl acetate and water, the organic layer waswashed with water and saturated brine and dried over anhydrous magnesiumsulfate, the drying agent was filtered off and the filtrate wasdistilled off under reduced pressure. The obtained crude product wassuspended in ethyl acetate, the suspension was diluted with hexane, andthe crystals were filtered out, washed with hexane and then blow-driedto obtain the title compound (98.0 mg, 0.305 mmol, 69%) as colorlesscrystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 5.66 (1H, s), 6.81 (2H, brs),6.94-6.99 (1H, m), 7.03-7.08 (2H, m), 7.25-7.32 (2H, m), 7.43-7.52 (4H,m), 8.07 (1H, s), 8.74 (1H, s), 8.80 (1H, s).

The intermediates were synthesized in the following manner.

Production Example 551-1 4-Chloro-6-(4-nitrophenoxy)pyrimidine

2,4-Dichloropyrimidine (2.98 g, 20.0 mmol), 4-nitrophenol (2.78 g, 20.0mmol) and potassium carbonate (4.15 g, 30.0 mmol) were stirred togetherin dimethylformamide (20 ml) at room temperature for 15 hours. Thereaction solution was distributed between ethyl acetate and water, theorganic layer was washed with water and saturated brine and dried overanhydrous magnesium sulfate, the drying agent was filtered off and thefiltrate was distilled off under reduced pressure. The obtained crudeproduct was subjected to silica gel column chromatography (eluent—ethylacetate:hexane=1:4), and the fraction containing the target substancewas concentrated to obtain the title compound (3.89 g, 15.5 mmol, 77%)as colorless crystals.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 7.08 (1H, d, J=0.6 Hz), 7.32-7.37 (2H,m), 8.32-8.37 (2H, m), 8.60 (1H, d, J=0.6 Hz).

Production Example 551-2 6-(4-Nitrophenoxy)pyrimidin-4-ylamine

4-Chloro-6-(4-nitrophenoxy)pyrimidine (1.04 g, 4.00 mmol) was heated andstirred in an ammonia-ethanol solution (14%, 10 ml) at 110° C. for 15minutes using an autoclave. The reaction solution was distributedbetween ethyl acetate and water, the organic layer was washed with 1Naqueous sodium hydroxide, water and saturated brine and dried overanhydrous magnesium sulfate, the drying agent was filtered off and thefiltrate was distilled off under reduced pressure. The obtained crudeproduct was subjected to silica gel column chromatography (eluent—ethylacetate:hexane=1:1), and the fraction containing the target substancewas concentrated to obtain the title compound (306 mg, 1.32 mmol, 33%)as colorless crystals.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 5.00 (2H, br s), 6.03 (1H, s),7.25-7.32 (2H, m), 8.26-8.33 (3H, m).

Production Example 551-3 6-(4-Aminophenoxy)pyrimidin-4-ylamine

After suspending 6-(4-nitrophenoxy)pyrimidin-4-ylamine (306 mg, 1.32mmol), iron powder (369 mg, 6.60 mmol) and ammonium chloride (706 mg,13.2 mmol) in an ethanol (20 ml)—water (5 ml) mixed solvent, thesuspension was heated and stirred at 80° C. for 20 minutes. Aftercompletion of the reaction, the reaction mixture was filtered withcelite and washed in ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate, the dryingagent was filtered off and the filtrate was concentrated to obtain thetitle compound (266 mg, 1.32 mmol, 100%) as light yellow crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 5.05 (2H, br s), 5.55 (1H, s),6.57-6.62 (2H, m), 6.73 (2H, br s), 6.77-6.82 (2H, m), 8.04 (1H, s).

Example 552 N-(6-(4-(3-Phenylureido)phenoxy)pyrimidin-4-yl)acetamide

N-(4-(6-Aminopyrimidin-4-yloxy)phenyl)-N′-phenylurea (60.0 mg, 0.187mmol) was heated and stirred in an acetic anhydride (1 ml)—pyridine (1ml) mixed solvent at 60° C. for 18 hours. After returning the reactionsolution to room temperature, it was poured into water and theprecipitated crystals were filtered out, washed with water and methanoland blow-dried to obtain the title compound (35.0 mg, 0.096 mmol, 52%)as colorless crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.11 (3H, s), 6.94-7.00 (1H, m),7.10-7.15 (2H, m), 7.25-7.31 (2H, m), 7.44-7.54 (5H, m), 8.49 (1H, d,J=0.4 Hz), 8.72 (1H, s), 8.80 (1H, s), 10.94 (1H, s).

Example 553N-(4-(6-Aminopyrimidin-4-yloxy)phenyl)-N′-(4-fluorophenyl)urea

The title compound (100 mg, 0.295 mmol, 65%) was obtained as colorlesscrystals from 6-(4-aminophenoxy)pyrimidin-4-ylamine (88.9 mg, 0.440mmol) and 4-fluorophenyl isocyanate (60.3 mg, 0.440 mmol), by the sameprocedure as in Example 551.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 5.66 (1H, d, J=0.6 Hz), 6.81 (2H, brs), 7.04-7.15 (4H, m), 7.44-7.52 (4H, m), 8.07 (1H, d, J=0.6 Hz), 8.84(1H, s), 8.85 (1H, s).

Example 554N-(6-(4-(3-(4-Fluorophenyl)ureido)phenoxy)pyrimidin-4-yl)acetamide

The title compound (56 mg, 0.147 mmol, 79%) was obtained as colorlesscrystals fromN-(4-(6-aminopyrimidin-4-yloxy)phenyl)-N′-(4-fluorophenyl)urea (60.0 mg,0.176 mmol), by the same procedure as in Example 552.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.11 (3H, s), 7.09-7.16 (4H, m),7.44-7.54 (5H, m), 8.49 (1H, s), 8.80 (1H, s), 8.83 (1H, s), 10.94 (1H,s).

Example 555N-(4-(6-Aminopyrimidin-4-yloxy)phenyl)-N′-(3-methanesulfonylphenyl)urea

6-(4-Aminophenoxy)pyrimidin-4-ylamine (88.9 mg, 0.440 mmol) and(3-methylsulfonylphenyl)carbamic acid phenyl ester (128 mg, 0.440 mmol)were stirred in dimethylsulfoxide (2 ml) at 85° C. for 18 hours. Thereaction solution was distributed between ethyl acetate and water, theorganic layer was washed with 1N aqueous sodium hydroxide, water andsaturated brine and dried over anhydrous magnesium sulfate, the dryingagent was filtered off and the filtrate was distilled off under reducedpressure. The obtained crude product was subjected to silica gel columnchromatography (eluent—ethyl acetate:methanol=30:1), the fractioncontaining the target substance was concentrated and suspended in ethylacetate, the suspension was diluted with hexane and the crystals werefiltered out, washed with hexane and blow-dried to obtain the titlecompound (75.0 mg, 0.188 mmol, 43%) as colorless crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.20 (3H, s), 5.67 (1H, s), 6.82 (2H,br s), 7.04-7.12 (2H, m), 7.44-7.59 (4H, m), 7.65-7.70 (1H, m), 8.07(1H, s), 8.16-8.19 (1H, m), 8.92 (1H, br s), 9.19 (1H, br s).

Example 556N-(6-(4-(3-(3-Methylsulfonylphenyl)ureido)phenoxy)pyrimidin-4-yl)acetamide

The title compound (13 mg, 0.029 mmol, 24%) was obtained as colorlesscrystals fromN-(4-(6-aminopyrimidin-4-yloxy)phenyl)-N′-(3-methylsulfonylphenyl)urea(50.0 mg, 0.125 mmol), by the same procedure as in Example 552.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.11 (3H, s), 3.20 (3H, s), 7.11-7.17(2H, m), 7.50-7.59 (5H, m), 7.66-7.70 (1H, m), 8.16-8.19 (1H, m), 8.50(1H, s), 9.01 (1H, br s), 9.28 (1H, br s), 10.95 (1H, s).

Example 557 N-(4-(2-Aminopyrimidin-4-yloxy)phenyl)-N′-phenylurea

The title compound (105 mg, 0.327 mmol, 65%) was obtained as colorlesscrystals from 4-(4-aminophenoxy)pyrimidin-2-ylamine (101 mg, 0.500 mmol)and phenyl isocyanate (59.6 mg, 0.500 mmol), by the same procedure as inExample 551.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 6.07 (1H, d, J=5.8 Hz), 6.61 (2H, brs), 6.94-6.99 (1H, m), 7.05-7.10 (2H, m), 7.25-7.31 (2H, m), 7.43-7.51(4H, m), 8.08 (1H, d, J=5.8 Hz), 8.74 (1H, br s), 8.79 (1H, br s).

The intermediates were synthesized in the following manner.

Production Example 557-1 4-Chloro-6-(4-nitrophenoxy)pyrimidin-2-ylamine

2-Amino-4,6-dichloropyrimidine (3.28 g, 20.0 mmol), 4-nitrophenol (2.78g, 20.0 mmol), and potassium carbonate (4.15 g, 30.0 mmol) were heatedand stirred in dimethylformamide (20 ml) at 100° C. for 3 hours. Afterreturning the reaction solution to room temperature, it was poured intoice water (100 ml) and the precipitated crystals were filtered out,washed with water and blow-dried to obtain the title compound (4.93 g,18.5 mmol, 92%) as colorless crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 6.43 (1H, s), 7.25 (2H, br s),7.46-7.52 (2H, m), 8.28-8.34 (2H, m).

Production Example 557-2 4-(4-Aminophenoxy)pyrimidin-2-ylamine

After suspending 4-chloro-6-(4-nitrophenoxy)pyrimidin-2-ylamine (1.60 g,1.32 mmol) in a methanol (30 ml)—tetrahydrofuran (30 ml) mixed solvent,palladium hydroxide-carbon (300 mg) was added and the mixture wasstirred at room temperature for 18 hours under a hydrogen atmosphere.The catalyst was filtered off by celite filtration, and after washingwith ethanol, the filtrate was distilled off under reduced pressure. Theobtained crude product was subjected to silica gel column chromatography(eluent—ethyl acetate:hexane=3:1), and the fraction containing thetarget substance was concentrated to obtain the title compound (910 mg,4.50 mmol, 75%) as colorless crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 5.01 (2H, br s), 5.93 (1H, d, J=5.4Hz), 6.50-6.60 (4H, m), 6.76-6.82 (2H, m), 8.03 (1H, d, J=5.4 Hz).

Example 558N-(4-(2-Aminopyrimidin-4-yloxy)phenyl)-N′-(4-fluorophenyl)urea

The title compound (105 mg, 0.309 mmol, 62%) was obtained as colorlesscrystals from 4-(4-aminophenoxy)pyrimidin-2-ylamine (101 mg, 0.500 mmol)and 4-fluorophenyl isocyanate (68.6 mg, 0.500 mmol), by the sameprocedure as in Example 551.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 6.06 (1H, d, J=5.6 Hz), 6.61 (2H, brs), 7.05-7.15 (4H, m), 7.44-7.52 (4H, m), 8.08 (1H, d, J=5.6 Hz),8.75-8.79 (2H, m).

Example 559N-(4-(2-Aminopyrimidin-4-yloxy)phenyl)-N′-(3-methylsulfonylphenyl)urea

The title compound (96 mg, 0.240 mmol, 48%) was obtained as colorlesscrystals from 4-(4-aminophenoxy)pyrimidin-2-ylamine (101 mg, 0.500 mmol)and (3-methylsulfonylphenyl)carbamic acid phenyl ester (146 mg, 0.500mmol), by the same procedure as in Example 555.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.20 (3H, s), 6.07 (1H, d, J=5.8 Hz),6.61 (2H, br s), 7.06-7.12 (2H, m), 7.46-7.59 (4H, m), 7.65-7.70 (1H,m), 8.09 (1H, d, J=5.8 Hz), 8.16-8.19 (1H, m), 8.89 (1H, br s), 9.18(1H, br s).

Example 5604-(3-Fluoro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxamide

The title compound (22 mg) was obtained as light yellow crystals fromphenylN-(4-(6-carbamoyl-7-(2-methoxyethoxy)-4-quinolyl)oxy-2-fluorophenyl)carbamate,which was obtained from4-(4-amino-3-fluorophenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxamide(100 mg) by the same procedure as in Example 11, and cyclopropylamine.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.39 (2H, m), 0.63 (2H, m), 2.49 (1H,m), 3.30 (3H, s), 3.79 (2H, m), 4.39 (2H, m), 6.51 (1H, d, J=5.2 Hz),6.79 (1H, s), 7.06 (1H, m), 7.31 (1H, m), 7.54 (1H, s), 7.79 (1H, s),7.83 (1H, s), 8.18-8.22 (2H, m), 8.65 (1H, d, J=5.2 Hz), 8.74 (1H, s).

Example 5611-[4-(7-Benzyloxy-6-cyanoquinolin-4-yloxy)-2-methylphenyl]-3-cyclopropylurea

A carbamate (1.73 g) was obtained as a solid from4-(4-amino-2-methylphenoxy)-7-benzyloxyquinoline-6-carbonitrile (2 g)and phenyl chlorocarbonate, in the same manner as Production Example 17.The carbamate (1.7 g) was then treated with cyclopropylamine indimethylsulfoxide at room temperature in the same manner as Example 11,to obtain the title compound (1.4 g) as a solid.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.37-0.41 (2H, m), 0.59-0.64 (2H, m),2.23 (3H. s), 2.50-2.56 (1H, m), 5.42 (2H, s), 6.49 (1H, d, J=5.2 Hz),6.73-6.75 (1H, m), 7.02 (1H, dd, J=2.8 Hz, J=8.8 Hz), 7.08 (1H, d, J=2.8Hz), 7.32-7.53 (5H, m), 7.60 (1H, s), 7.66 (1H, s), 7.89 (1H, d, J=8.8Hz), 8.68 (1H, d, J=5.2 Hz), 8.73 (1H, s).

The intermediate was synthesized in the following manner.

Production Example 561-14-(4-Amino-3-methylphenoxy)-7-benzyloxyquinoline-6-carbonitrile

The title compound (3.6 g) was obtained as a solid from7-benzyloxy-4-chloroquinoline-6-carbonitrile (5 g) and4-amino-3-methylphenol, in the same manner as Production Example 395-1.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.07 (3H, s), 4.94 (2H, s), 5.43 (2H,s), 6.46 (1H, d, J=5, 2 Hz), 6.69 (1H, d, J=8.8 Hz), 6.82 (1H, dd, J=2.8Hz, J=8.8 Hz), 6.87 (1H, d, J=2.8 Hz), 7.36 (1H, t, J=7.2 Hz), 7.44 (2H,t, J=7.2 Hz), 7.53 (2H, d, J=7.2 Hz), 7.66 (1H, s), 8.67 (1H, d, J=5.2Hz), 8.73 (1H, s).

Example 5621-[4-(6-Cyano-7-hydroxyquinolin-4-yloxy)-2-methylphenyl]-3-cyclopropylurea

In the same manner as Production Example 301-2,1-[4-(7-benzyloxy-6-cyano-quinolin-4-yloxy)-2-methyl-phenyl]-3-cyclopropyl-urea(0.8 g) was debenzylated in tetrahydrofuran using palladium-carbon, toobtain the title compound (0.5 g) as a solid.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.36-0.41 (2H, m), 0.59-0.65 (2H, m),2.17 (3H, s), 2.49-2.56 (1H, m), 6.32 (1H, d, J=5.2 Hz), 6.74 (1H, d,J=2.8 Hz), 7.01 (1H, dd, J=2.4 Hz, J=8.8 Hz), 7.07 (1H, d, J=2.4 Hz),7.30 (1H, s), 7.59 (1H, s), 7.90 (1H, d, J=8.8 Hz), 8.56 (1H, d, J=5.2Hz), 8.57 (1H, s).

Example 5631-[4-(6-Cyano-(2R)-7-oxiranylmethoxyquinolin-4-yloxy)-2-methylphenyl]-3-cyclopropylurea

The title compound (312 mg) was obtained as a solid from1-[4-(6-cyano-7-hydroxyquinolin-4-yloxy)-2-methylphenyl]-3-cyclopropylurea(500 mg), in the same manner as Production Example 284-1.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.37-0.42 (2H, m), 0.59-0.65 (2H, m),2.18 (3H, s), 2.49-2.56 (1H, m), 2.78-2.81 (1H, m), 2.89 (1H, t, J=4.8Hz), 3.42-3.47 (1H, m), 4.14 (1H, dd, J=6.4 Hz, J=11.6 Hz), 4.68 (1H,dd, J=2.4 Hz, J=11.6 Hz), 6.49 (1H, d, J=5.2 Hz), 6.74 (1H, d, J=2.4Hz), 7.03 (1H, dd, J=2.4 Hz, J=8.4 Hz), 7.09 (1H, d, J=2.4 Hz), 7.59(1H, s), 7.61 (1H, s), 7.92 (1H, d, J=8.4 Hz), 8.70 (1H, d, J=5.2 Hz),8.74 (1H, s).

Example 5641-{4-[6-Cyano-7-((2R)-2-hydroxy-3-pyrrolidin-1-yl-propoxy)quinolin-4-yloxy]-2-methyl-phenyl}-3-cyclopropyl-urea

The title compound (11 mg) was obtained as a solid from1-[4-(6-cyano-7-(2R)-oxiranylmethoxyquinolin-4-yloxy)-2-methylphenyl]-3-cyclopropyl-urea(55 mg) and pyrrolidine, in the same manner as Example 284.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.37-0.41 (2H, m), 0.58-0.65 (2H, m),2.26 (3H, s), 1.62-1.69 (4H, m), 2.44-2.56 (6H, m), 2.68 (1H, dd, J=6.4Hz, J=12 Hz), 3.96-4.03 (1H, m), 4.18 (1H, dd, J=5.6 Hz, J=10.4 Hz),4.28 (1H, dd, J=3.6 Hz, J=10.4 Hz), 5.00 (1H, d, J=5.2 Hz), 6.48 (1H, d,J=5.2 Hz), 6.75 (1H, d, J=2.4 Hz), 7.03 (1H, dd, J=2.4 Hz, J=8.8 Hz),7.09 (1H, d, J=2.4 Hz), 7.58 (1H, s), 7.60 (1H, s), 7.91 (1H, d, J=8.8Hz), 8.68 (1H, d, J=5.2 Hz), 8.71 (1H, s).

Example 5651-{4-[6-Cyano-7-((2R)-2-hydroxy-3-piperidin-1-ylpropoxy)quinolin-4-yloxy]-2-methylphenyl}-3-cyclopropyl-urea

The title compound (8 mg) was obtained as a solid from[1-[4-(6-cyano-(2R)-7-oxiranylmethoxyquinolin-4-yloxy)-2-methylphenyl]-3-cyclopropylurea(100 mg) and piperidine, in the same manner as Example 284.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.37-0.41 (2H, m), 0.59-0.66 (2H, m),1.31-1.38 (2H, m), 1.43-1.53 (4H, m), 2.20 (3H, s), 2.33-2.58 (7H, m),3.99-4.06 (1H, m), 4.19 (1H, dd, J=5.6 Hz, J=10.4 Hz), 4.29 (1H, dd,J=3.2 Hz, J=10.4 Hz), 4.94 (1H, br), 6.49 (1H, d, J=5.2 Hz), 6.75-6.79(1H, m), 7.02-7.08 (1H, m), 7.09-7.13 (1H, m), 7.60 (1H, s), 7.62 (1H,s), 7.93 (1H, d, J=9.2 Hz), 8.70 (1H, d, J=5.2 Hz), 8.71 (1H, s).

Example 5661-{4-[6-Cyano-7-(3-diethylamino-(2R)-2-hydroxy-propoxy)quinolin-4-yloxy]-2-methyl-phenyl}-3-cyclopropyl-urea

The title compound (21 mg) was obtained as a solid from[1-[4-(6-cyano-(2R)-7-oxiranylmethoxyquinolin-4-yloxy)-2-methylphenyl]-3-cyclopropylurea(55 mg) and diethylamine, in the same manner as Example 284.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.37-0.41 (2H, m), 0.59-0.65 (2H, m),0.91-1.00 (6H, m), 2.18 (3H, s), 2.43-2.69 (7H, m), 3.91-4.00 (1H, m),4.17-4.22 (1H, m), 4.26-4.31 (1H, m), 6.48 (1H, d, J=5.2 Hz), 6.76 (1H,d, J=2.8 Hz), 7.03 (1H, dd, J=2.8 Hz, J=8.8 Hz), 7.09 (1H, d, J=2.4 Hz),7.58 (1H, s), 7.60 (1H, s), 7.91 (1H, d, J=8.8 Hz), 8.68 (1H, d, J=5.2Hz), 8.71 (1H, s).

Example 5671-{4-[6-Cyano-7-(3-pyrrolidin-1-ylpropoxy)quinolin-4-yloxy]-2-methylphenyl}-3-cyclopropylurea

The title compound (23 mg) was obtained as a solid from1-[4-(6-cyano-7-hydroxyquinolin-4-yloxy)-2-methylphenyl]-3-cyclopropylurea(60 mg) and 1-(3-chloropropyl)pyrrolidine, in the same manner as Example7.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.37-0.41 (2H, m), 0.59-0.65 (2H, m),1.62-1.69 (4H, m), 1.93-2.01 (2H, m), 2.18 (3H, s), 2.39-2.45 (4H, m),2.49-2.55 (1H, m), 2.57 (2H, t, J=7.2 Hz), 4.30 (2H, t, J=6.4 Hz), 6.48(1H, d, J=5.2 Hz), 6.75 (1H, d, J=2.8 Hz), 7.03 (1H, dd, J=2.8 Hz, J=8.8Hz), 7.08 (1H, d, J=2.8 Hz), 7.55 (1H, s), 7.60 (1H, s), 7.91 (1H, d,J=8.8 Hz), 8.68 (1H, d, J=5.2 Hz), 8.71 (1H, s).

Example 568 N-Phenyl-N′-(4-(6-phenylaminopyrimidin-4-yloxy)phenyl)urea

N-(6-(4-Aminophenoxy)pyrimidin-4-yl)phenylamine (55.6 mg, 0.200 mmol)and phenyl isocyanate (26.1 mg, 0.220 mmol) were stirred together indimethylformamide (1 ml) at room temperature for 12 hours. The reactionsolution was distributed between ethyl acetate and water, the organiclayer was washed with water and saturated brine and dried over anhydrousmagnesium sulfate, the drying agent was filtered off and the filtratewas distilled off under reduced pressure. The obtained crude product wassuspended in ethyl acetate, the suspension was diluted with hexane, andthe crystals were filtered out, washed with hexane and then blow-driedto obtain the title compound (69.0 mg, 0.174 mmol, 87%) as colorlesscrystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 6.06 (1H, d, J=1.6 Hz), 6.95-7.02(2H, m), 7.11-7.16 (2H, m), 7.25-7.34 (4H, m), 7.44-7.50 (2H, m),7.50-7.56 (2H, m), 7.58-7.63 (2H, m), 8.35 (1H, d, J=1.6 Hz), 8.71 (1H,s), 8.79 (1H, s), 9.54 (1H, s).

The intermediates were synthesized in the following manner.

Production Example 568-1 N-(6-(4-Nitrophenoxy)pyrimidin-4-yl)phenylamine

4-Chloro-6-(4-nitrophenoxy)pyrimidine (508 mg, 2.00 mmol) and aniline(559 mg, 6.00 mmol) were heated and stirred in 1-methylpyrrolidone (5ml) at 90° C. for 3 hours. The reaction solution was distributed betweenethyl acetate and water, the organic layer was washed with water andsaturated brine and dried over anhydrous magnesium sulfate, the dryingagent was filtered off and the filtrate was distilled off under reducedpressure. The obtained crude product was subjected to silica gel columnchromatography (eluent—ethyl acetate:hexane=1:3), and the fractioncontaining the target substance was concentrated to obtain the titlecompound (508 mg, 1.65 mmol, 82%) as colorless crystals.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 6.34 (1H, s), 7.03 (1H, br s),7.21-7.35 (5H, m), 7.40-7.46 (2H, m), 8.26-8.32 (2H, m), 8.35 (1H, s).

Production Example 568-2 N-(6-(4-Aminophenoxy)pyrimidin-4-yl)phenylamine

After suspending N-(6-(4-nitrophenoxy)pyrimidin-4-yl)phenylamine (508mg, 1.65 mmol), iron powder (461 mg, 8.25 mmol) and ammonium chloride(882 mg, 16.5 mmol) in an ethanol (16 ml)—water (4 ml) mixed solvent,the suspension was heated and stirred at 80° C. for 20 minutes. Uponcompletion of the reaction, the reaction mixture was filtered withcelite and washed in ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate, the dryingagent was filtered off and the filtrate was distilled off under reducedpressure. The obtained crude product was suspended in ethyl acetate, thesuspension was diluted with hexane, and the crystals were filtered out,washed with hexane and then blow-dried to obtain the title compound (387mg, 1.39 mmol, 84%) as colorless crystals.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 3.64 (2H, br s), 6.17 (1H, d, J=0.8Hz), 6.67-6.73 (2H, m), 6.77 (1H, br s), 6.89-6.95 (2H, m), 7.14-7.20(1H, m), 7.26-7.32 (2H, m), 7.35-7.41 (2H, m), 8.37 (1H, d, J=0.8 Hz).

Example 569N-(3-Methylsulfonylphenyl)-N′-(4-(6-phenylaminopyrimidin-4-yloxy)phenyl)urea

N-(6-(4-Aminophenoxy)pyrimidin-4-yl)phenylamine (55.6 mg, 0.200 mmol)and (3-methylsulfonylphenyl)carbamic acid phenyl ester (63.8 mg, 0.220mmol) were heated and stirred in dimethylsulfoxide (1 ml) at 85° C. for2 hours. The reaction solution was distributed between ethyl acetate andwater, the organic layer was washed with 1N aqueous sodium hydroxide,water and saturated brine and dried over anhydrous magnesium sulfate,the drying agent was filtered off and the filtrate was distilled offunder reduced pressure. The obtained crude product was suspended inethyl acetate, the suspension was diluted with hexane, and the crystalswere filtered out, washed with hexane and then blow-dried to obtain thetitle compound (77.0 mg, 0.162 mmol, 81%) as colorless crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.20 (3H, s), 6.07 (1H, s), 6.98-7.03(1H, m), 7.12-7.17 (2H, m), 7.28-7.34 (2H, m), 7.50-7.63 (6H, m),7.66-7.72 (1H, m), 8.17-8.20 (1H, m), 8.34 (1H, s), 8.93 (1H, br s),9.19 (1H, br s), 9.54 (1H, s).

Example 570N-(4-(6-(4-Methylsulfanylphenylamino)pyrimidin-4-yloxy)phenyl)-N′-phenylurea

N-(6-(4-Aminophenoxy)pyrimidin-4-yl)-4-methylsulfanylphenylamine (194mg, 0.600 mmol) and phenyl isocyanate (78.6 mg, 0.660 mmol) were stirredin dimethylformamide (2 ml) at room temperature for 18 hours. Thereaction solution was distributed between ethyl acetate and water, theorganic layer was washed with water and saturated brine and dried overanhydrous magnesium sulfate, the drying agent was filtered off and thefiltrate was distilled off under reduced pressure. The obtained crudeproduct was suspended in ethyl acetate, the suspension was diluted withhexane, and the crystals were filtered out, washed with hexane and thenblow-dried to obtain the title compound (250 mg, 0.564 mmol, 94%) ascolorless crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.44 (3H, s), 6.03 (1H, d, J=1.6 Hz),6.95-7.00 (1H, m), 7.10-7.15 (2H, m), 7.22-7.32 (4H, m), 7.44-7.50 (2H,m), 7.50-7.60 (4H, m), 8.34 (1H, d, J=1.6 Hz), 8.73 (1H, br s), 8.81(1H, br s), 9.56 (1H, s).

The intermediates were synthesized in the following manner.

Production Example 570-1N-(6-(4-Nitrophenoxy)pyrimidin-4-yl)-4-methylsulfanylphenylamine

4-Chloro-6-(4-nitrophenoxy)pyrimidine (2.33 g, 9.25 mmol),4-(methylthio)aniline (1.29 g, 9.25 mmol) and diisopropylethylamine(1.79 g, 13.9 mmol) were heated and stirred in 1-methylpyrrolidone (10ml) at 80° C. for 18 hours. The reaction solution was distributedbetween ethyl acetate and water, the organic layer was washed with 1Naqueous sodium hydroxide, water and saturated brine and dried overanhydrous magnesium sulfate, the drying agent was filtered off and thefiltrate was distilled off under reduced pressure. The obtained crudeproduct was subjected to silica gel column chromatography (eluent—ethylacetate:hexane=1:3), the fraction containing the target substance wasconcentrated and suspended in ethyl acetate, the suspension was dilutedwith hexane and the crystals were filtered out, washed with hexane andblow-dried to obtain the title compound (620 mg, 1.75 mmol, 19%) ascolorless crystals.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 2.51 (3H, s), 6.28 (1H, d, J=1.0 Hz),6.99 (1H, br s), 7.23-7.34 (6H, m), 8.26-8.32 (2H, m), 8.34 (1H, d,J=1.0 Hz).

Production Example 570-2N-(6-(4-Aminophenoxy)pyrimidin-4-yl)-4-methylsulfanylphenylamine

N-(6-(4-Nitrophenoxy)pyrimidin-4-yl)-4-methylsulfanylphenylamine (620mg, 1.75 mmol), iron powder (489 mg, 8.75 mmol) and ammonium chloride(936 mg, 17.5 mmol) were suspended in an ethanol (16 ml)—water (4 ml)mixed solvent and the suspension was heated and stirred at 80° C. for 1hour. Upon completion of the reaction, the reaction mixture was filteredwith celite and washed in an ethyl acetate-tetrahydrofuran mixedsolvent. The organic layer was washed with water and saturated brine anddried over anhydrous magnesium sulfate, the drying agent was filteredoff and the filtrate was distilled off under reduced pressure. Theobtained crude product was suspended in ethyl acetate, the suspensionwas diluted with hexane, and the crystals were filtered out, washed withhexane and then blow-dried to obtain the title compound (392 mg, 1.21mmol, 69%) as colorless crystals.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 2.49 (3H, s), 3.65 (2H, br s), 6.10(1H, d, J=1.0 Hz), 6.66-6.72 (2H, m), 6.76 (1H, br s), 6.88-6.94 (2H,m), 7.21-7.30 (4H, m), 8.35 (1H, d, J=1.0 Hz).

Example 571N-(3-Methylsulfonylphenyl)-N′-(4-(6-(4-methylsulfanylphenylamino)pyrimidin-4-yloxy)phenyl)urea

N-(6-(4-Aminophenoxy)pyrimidin-4-yl)-4-methylsulfanylphenylamine (194mg, 0.600 mmol) and (3-methylsulfonylphenyl)carbamic acid phenyl ester(192 mg, 0.660 mmol) were heated and stirred in dimethylsulfoxide (2 ml)at 85° C. for 18 hours. The reaction solution was distributed betweenethyl acetate and water, the organic layer was washed with water andsaturated brine and dried over anhydrous magnesium sulfate, the dryingagent was filtered off and the filtrate was distilled off under reducedpressure. The obtained crude product was subjected to silica gel columnchromatography (eluent—ethyl acetate), the fraction containing thetarget substance was concentrated and suspended in ethyl acetate, thesuspension was diluted with hexane and the crystals were filtered out,washed with hexane and blow-dried to obtain the title compound (297 mg,0.569 mmol, 95%) as colorless crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.44 (3H, s), 3.20 (3H, s), 6.04 (1H,d, J=0.8 Hz), 7.12-7.17 (2H, m), 7.22-7.27 (2H, m), 7.50-7.63 (6H, m),7.67-7.71 (1H, m), 8.17-8.20 (1H, m), 8.34 (1H, d, J=0.8 Hz), 8.92 (1H,s), 9.17 (1H, s), 9.56 (1H, s).

Example 572N-(4-(6-(4-Methylsulfonylphenylamino)pyrimidin-4-yloxy)phenyl)-N′-phenylurea

N-(4-(6-(4-Methylsulfanylphenylamino)pyrimidin-4-yloxy)phenyl)-N′-phenylurea(180 mg, 0.406 mmol) and 3-chloroperbenzoic acid (200 mg, 0.812 mmol)were stirred in dichloromethane (6 ml) at room temperature for 12 hours.A saturated aqueous sodium thiosulfate solution was added to suspend thereaction, and then the reaction solution was distributed between ethylacetate and water, the organic layer was washed with 1N aqueous sodiumhydroxide, water and saturated brine and dried over anhydrous magnesiumsulfate, the drying agent was filtered off and the filtrate wasdistilled off under reduced pressure. The obtained crude product wassubjected to silica gel column chromatography (eluent—ethylacetate:hexane=3:1), the fraction containing the target substance wasconcentrated and suspended in ethyl acetate, the suspension was dilutedwith hexane and the crystals were filtered out, washed with hexane andblow-dried to obtain the title compound (137 mg, 0.288 mmol, 71%) ascolorless crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.16 (3H, s), 6.18 (1H, s), 6.97-7.02(1H, m), 7.13-7.19 (2H, m), 7.27-7.33 (2H, m), 7.46-7.51 (2H, m),7.53-7.59 (2H, m), 7.81-7.87 (2H, m), 7.89-7.94 (2H, m), 8.47 (1H, s),8.72 (1H, s), 8.81 (1H, s), 10.06 (1H, s).

Example 573N-(3-Methylsulfonylphenyl)-N′-(4-(6-(4-methylsulfonylphenylamino)pyrimidin-4-yloxy)phenyl)urea

The title compound (157 mg, 0.284 mmol, 64%) was obtained as colorlesscrystals fromN-(3-methylsulfonylphenyl)-N′-(4-(6-(4-methylsulfanylphenylamino)pyrimidin-4-yloxy)phenyl)urea(230 mg, 0.441 mmol), by the same procedure as in Example 572.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.16 (3H, s), 3.20 (3H, s), 6.19 (1H,d, J=1.0 Hz), 7.04-7.10 (2H, m), 7.50-7.60 (4H, m), 7.66-7.70 (1H, m),7.82-7.88 (2H, m), 7.88-7.94 (2H, m), 8.17-8.20 (1H, m), 8.47 (1H, d,J=1.0 Hz), 8.95 (1H, s), 9.19 (1H, s), 10.06 (1H, s).

Example 574N-(4-(6-(4-Fluorophenylamino)pyrimidin-4-yloxy)phenyl)-N′-phenylurea

N-(4-(6-Chloropyrimidin-4-yloxy)phenyl)-N′-phenylurea (68.0 mg, 0.200mmol) and 4-fluoroaniline (111 mg, 1.00 mmol) were heated and stirred in1-methylpyrrolidone (1 ml) at 130° C. for 3 hours. The reaction solutionwas distributed between ethyl acetate and water, the organic layer waswashed with saturated aqueous sodium bicarbonate, water and saturatedbrine and dried over anhydrous magnesium sulfate, the drying agent wasfiltered off and the filtrate was distilled off under reduced pressure.The obtained crude product was suspended in ethyl acetate, thesuspension was diluted with hexane, and the crystals were filtered out,washed with hexane and then blow-dried to obtain the title compound(33.0 mg, 0.079 mmol, 40%) as colorless crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 6.00 (1H, d, J=0.8 HZ), 6.95-7.00(1H, m), 7.10-7.19 (4H, m), 7.26-7.32 (2H, m), 7.44-7.50 (2H, m),7.50-7.56 (2H, m), 7.57-7.63 (2H, m), 8.33 (1H, d, J=0.8 Hz), 8.68 (1H,s), 8.76 (1H, s), 9.56 (1H, s).

The intermediates were synthesized in the following manner.

Production Example 574-1 4-(6-Chloropyrimidin-4-yloxy)phenylamine

4-Chloro-6-(4-nitrophenoxy)pyrimidine (2.52 g, 10.0 mmol), iron powder(2.79 g, 50.0 mmol) and ammonium chloride (5.35 g, 100 mmol) weresuspended in an ethanol (100 ml)—water (25 ml) mixed solvent and thesuspension was heated and stirred at 80° C. for 1 hour. Upon completionof the reaction, the reaction mixture was filtered with celite andwashed in an ethanol-ethyl acetate mixed solvent. The organic layer waswashed with water and saturated brine and dried over anhydrous magnesiumsulfate, the drying agent was filtered off and the filtrate wasdistilled off under reduced pressure. The obtained crude product wassubjected to silica gel column chromatography (eluent—ethylacetate:hexane=2:3), and the fraction containing the target substancewas concentrated to obtain the title compound (1.74 g, 7.85 mmol, 79%)as colorless crystals.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 3.71 (2H, br s), 6.70-6.75 (2H, m),6.84 (1H, s), 6.90-6.95 (2H, m), 8.60 (1H, s).

Production Example 574-2N-(4-(6-Chloropyrimidin-4-yloxy)phenyl)-N′-phenylurea

4-(6-Chloropyrimidin-4-yloxy)phenylamine (663 mg, 3.00 mmol) and phenylisocyanate (393 mg, 3.30 mmol) were stirred in dimethylformamide (5 ml)at room temperature for 18 hours. The reaction solution was poured intowater and the precipitated crystals were filtered out, washed with waterand ethanol and blow-dried to obtain the title compound (988 mg, 2.91mmol, 97%) as colorless crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 6.94-7.00 (1H, m), 7.14-7.20 (2H, m),7.25-7.32 (2H, m), 7.33 (1H, d, J=0.8 Hz), 7.43-7.49 (2H, m), 7.50-7.56(2H, m), 8.65 (1H, d, J=0.8 Hz), 8.70 (1H, s), 8.78 (1H, s).

Example 575N-(4-(6-(3-Fluorophenylamino)pyrimidin-4-yloxy)phenyl)-N′-phenylurea

N-(4-(6-Chloropyrimidin-4-yloxy)phenyl)-N′-phenylurea (68.0 mg, 0.200mmol) and 3-fluoroaniline (111 mg, 1.00 mmol) were heated and stirred in1-methylpyrrolidone (1 ml) at 150° C. for 90 minutes. The reactionsolution was distributed between ethyl acetate and water, the organiclayer was washed with saturated aqueous sodium bicarbonate, water andsaturated brine and dried over anhydrous magnesium sulfate, the dryingagent was filtered off and the filtrate was distilled off under reducedpressure. The obtained crude product was suspended in ethyl acetate, thesuspension was diluted with hexane, and the crystals were filtered out,washed with hexane and then blow-dried to obtain the title compound(43.0 mg, 0.104 mmol, 52%) as colorless crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 6.09 (1H, s), 6.77-6.83 (1H, m),6.95-7.00 (1H, m), 7.11-7.17 (2H, m), 7.26-7.36 (4H, m), 7.45-7.50 (2H,m), 7.50-7.55 (2H, m), 7.71-7.77 (1H, m), 8.42 (1H, s), 8.69 (1H, s),8.77 (1H, s), 9.76 (1H, s).

Example 576N-(4-(6-(2-Fluorophenylamino)pyrimidin-4-yloxy)phenyl)-N′-phenylurea

N-(4-(6-Chloropyrimidin-4-yloxy)phenyl)-N′-phenylurea (68.0 mg, 0.200mmol) and 2-fluoroaniline (111 mg, 1.00 mmol) were heated and stirred in1-methylpyrrolidone (1 ml) at 170° C. for 3 hours. The reaction solutionwas distributed between ethyl acetate and water, the organic layer waswashed with saturated aqueous sodium bicarbonate, water and saturatedbrine and dried over anhydrous magnesium sulfate, the drying agent wasfiltered off and the filtrate was distilled off under reduced pressure.The obtained crude product was subjected to silica gel columnchromatography (eluent—ethyl acetate:hexane=3:2), the fractioncontaining the target substance was concentrated and suspended in ethylacetate, the suspension was diluted with hexane and the crystals werefiltered out, washed with hexane and blow-dried to obtain the titlecompound (26.0 mg, 0.062 mmol, 31%) as colorless crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 6.17 (1H, d, J=0.8 Hz), 6.95-7.00(1H, m), 7.10-7.19 (4H, m), 7.22-7.32 (3H, m), 7.45-7.50 (2H, m),7.50-7.55 (2H, m), 7.86-7.93 (1H, m), 8.29 (1H, d, J=0.8 Hz), 8.69 (1H,s), 8.76 (1H, s), 9.32 (1H, s).

Example 577N-(4-(6-(3,5-Difluorophenylamino)pyrimidin-4-yloxy)phenyl)-N′-phenylurea

N-(4-(6-Chloropyrimidin-4-yloxy)phenyl)-N′-phenylurea (68.0 mg, 0.200mmol) and 3, 5-difluoroaniline (129 mg, 1.00 mmol) were heated andstirred in 1-methylpyrrolidone (1 ml) at 170° C. for 3 hours. Thereaction solution was distributed between ethyl acetate and water, theorganic layer was washed with saturated aqueous sodium bicarbonate,water and saturated brine and dried over anhydrous magnesium sulfate,the drying agent was filtered off and the filtrate was distilled offunder reduced pressure. The obtained crude product was subjected tosilica gel column chromatography (eluent—ethyl acetate:hexane=1:1), thefraction containing the target substance was concentrated and suspendedin ethyl acetate, the suspension was diluted with hexane and thecrystals were filtered out, washed with hexane and blow-dried to obtainthe title compound (17.5 mg, 0.040 mmol, 20%) as colorless crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 6.09 (1H, s), 6.77-6.85 (1H, m),6.95-7.00 (1H, m), 7.13-7.19 (2H, m), 7.27-7.33 (2H, m), 7.38-7.50 (4H,m), 7.50-7.58 (2H, m), 8.46 (1H, s), 8.69 (1H, s), 8.78 (1H, s), 9.94(1H, s).

Example 578N-Phenyl-N′-(4-(6-(3,4,5-trimethoxyphenylamino)pyrimidin-4-yloxy)phenyl)ureahydrochloride

N-(4-(6-Chloropyrimidin-4-yloxy)phenyl)-N′-phenylurea (68.0 mg, 0.200mmol) and 3,4,5-trimethoxyaniline (183 mg, 1.00 mmol) were heated andstirred in 1-methylpyrrolidone (1 ml) at 150° C. for 2 hours. Thereaction solution was distributed between ethyl acetate and water, theorganic layer was washed with saturated aqueous sodium bicarbonate,water and saturated brine and dried over anhydrous magnesium sulfate,the drying agent was filtered off and the filtrate was distilled offunder reduced pressure. The obtained crude product was subjected tosilica gel column chromatography (eluent—ethyl acetate:hexane=3:1), thefraction containing the target substance was concentrated, converted toa hydrochloride with 1N hydrochloric acid and suspended in methanol, thesuspension was diluted with ethyl acetate and the crystals were filteredout, washed with ethyl acetate and blow-dried to obtain the titlecompound (50.0 mg, 0.095 mmol, 48%) as light green crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.61 (3H, s), 3.74 (6H, s), 6.03 (1H,s), 6.90 (2H, s), 6.95-7.00 (1H, m), 7.10-7.16 (2H, m), 7.27-7.33 (2H,m), 7.45-7.50 (2H, m), 7.50-7.55 (2H, m), 8.36 (1H, s), 8.91 (1H, s),9.02 (1H, s), 9.55 (1H, s).

Example 5791-(4-(6-(N-Methyl-N-phenylamino)pyrimidin-4-yloxy)phenyl)-3-phenylurea

N-(4-(6-Chloropyrimidin-4-yloxy)phenyl)-N′-phenylurea (68.0 mg, 0.200mmol) and N-methylaniline (107 mg, 1.00 mmol) were heated and stirred in1-methylpyrrolidone (1 ml) at 130° C. for 36 hours. The reactionsolution was distributed between ethyl acetate and water, the organiclayer was washed with water and saturated brine and dried over anhydrousmagnesium sulfate, the drying agent was filtered off and the filtratewas distilled off under reduced pressure. The obtained crude product wassubjected to silica gel column chromatography (eluent—ethylacetate:hexane=1:1), the fraction containing the target substance wasconcentrated and suspended in ethyl acetate, the suspension was dilutedwith hexane and the crystals were filtered out, washed with hexane andblow-dried to obtain the title compound (38 mg, 0.092 mmol, 46%) ascolorless crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.42 (3H, s), 5.75 (1H, s), 6.95-7.03(3H, m), 7.25-7.38 (5H, m), 7.41-7.50 (6H, m), 8.27 (1H, s), 8.64 (1H,s), 8.68 (1H, s).

Example 580N-(5-Chloro-2-thiazolyl)-N′-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxy-2-fluorophenyl)urea

The title compound (66.0 mg, 0.128 mmol, 64%) was obtained as whitecrystals from4-(4-amino-3-fluorophenoxy)-6-cyano-7-(2-methoxyethoxy)quinoline (71.0mg, 0.200 mmol) and phenyl 5-chloro-2-thiazolylcarbamate prepared from2-amino-5-chlorothiazole and phenyl chloroformate, by the same procedureas in Example 145.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.38 (3H, s), 3.80 (2H, m), 4.43 (2H,m), 6.65 (1H, d, J=5.2 Hz), 7.20 (1H, m), 7.44 (1H, s), 7.47 (1H, m),7.66 (1H, s), 8.20 (1H, m), 8.76 (1H, d, J=5.2 Hz), 8.77 (1H, s), 9.02(1H, s), 11.01 (1H, s).

Example 581N-(4-(6-Cyano-7-(2-methoxyethoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-(4-cyclopropyl-2-thiazolyl)urea

The title compound (88.0 mg, 0.169 mmol, 85%) was obtained as whitecrystals from4-(4-amino-3-fluorophenoxy)-6-cyano-7-(2-methoxyethoxy)quinoline (71.0mg, 0.200 mmol) and phenyl 4-cyclopropyl-2-thiazolylcarbamate preparedfrom 2-amino-4-cyclopropylthiazole and phenyl chloroformate, by the sameprocedure as in Example 145.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.75 (2H, m), 0.84 (2H, m), 1.95 (1H,m), 3.38 (3H, s), 3.80 (2H, m), 4.44 (2H, m), 6.64 (1H, d, J=5.2 Hz),6.72 (1H, s), 7.19 (1H, m), 7.46 (1H, m), 7.66 (1H, s), 8.25 (1H, m),8.76 (1H, d, J=5.2 Hz), 8.77 (1H, s), 10.84 (1H, br s).

Example 5824-(3-Chloro-4-(methylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (65.0 mg, 0.162 mmol, 50%) was obtained as whitecrystals from phenylN-(4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2-chlorophenyl)carbamate (150mg, 0.324 mmol) and 40% methylamine (methanol solution), by the sameprocedure as in Example 11.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.68 (3H, d, J=4.4 Hz), 4.03 (3H, s),6.53 (1H, d, J=5.0 Hz), 6.88 (1H, q, J=4.4 Hz), 7.23 (1H, dd, J=2.8, 8.2Hz), 7.48 (1H, d, J=2.8 Hz), 7.52 (1H, s), 7.74 (1H, s), 7.86 (1H, s),8.12 (1H, s), 8.25 (1H, d, J=8.2 Hz), 8.67 (1H, s), 8.68 (1H, d, J=5.0Hz).

Example 5834-(3-Chloro-4-(ethylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (92.0 mg, 0.221 mmol, 68%) was obtained as whitecrystals from phenylN-(4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2-chlorophenyl)carbamate (150mg, 0.324 mmol) and 2 M ethylamine (tetrahydrofuran solution), by thesame procedure as in Example 11.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.08 (3H, t, J=7.2 Hz), 3.14 (2H, m),4.03 (3H, s), 6.53 (1H, d, J=5.2 Hz), 6.99 (1H, t, J=5.6 Hz), 7.23 (1H,dd, J=2.8, 8.8 Hz), 7.48 (1H, d, J=2.8 Hz), 7.52 (1H, s), 7.73 (1H, s),7.85 (1H, s), 8.07 (1H, s), 8.27 (1H, d, J=8.8 Hz), 8.66 (1H, s), 8.67(1H, d, J=5.2 Hz).

Example 5844-(3-Chloro-4-(1-propylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (111 mg, 0.258 mmol, 80%) was obtained as whitecrystals from phenylN-(4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2-chlorophenyl)carbamate (150mg, 0.324 mmol) and propylamine, by the same procedure as in Example 11.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.91 (3H, t, J=7.4 Hz), 1.47 (2H, m),3.08 (2H, m), 4.03 (3H, s), 6.53 (1H, d, J=5.2 Hz), 7.03 (1H, t, J=5.6Hz), 7.23 (1H, dd, J=2.8, 8.8 Hz), 7.48 (1H, d, J=2.8 Hz), 7.52 (1H, s),7.74 (1H, s), 7.85 (1H, s), 8.09 (1H, s), 8.28 (1H, d, J=8.8 Hz), 8.66(1H, s), 8.67 (1H, d, J=5.2 Hz).

Example 5854-(3-Chloro-4-(cyanomethylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (107 mg, 0.251 mmol, 77%) was obtained as whitecrystals from phenylN-(4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2-chlorophenyl)carbamate (150mg, 0.324 mmol) and 2-aminoacetonitrile hydrochloride, by the sameprocedure as in Example 11.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 4.03 (3H, s), 4.22 (2H, t, J=6.0 Hz),6.56 (1H, d, J=5.2 Hz), 7.28 (1H, dd, J=2.8, 8.8 Hz), 7.50 (1H, t, J=6.0Hz), 7.53 (1H, s), 7.54 (1H, d, J=2.8 Hz), 7.74 (1H, s), 7.86 (1H, s),8.17 (1H, d, J=8.8 Hz), 8.51 (1H, s), 8.66 (1H, s), 8.68 (1H, d, J=5.2Hz).

Example 5864-(3-Chloro-4-(2-cyanoethylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (109 mg, 0.248 mmol, 76%) was obtained as whitecrystals from phenylN-(4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2-chlorophenyl)carbamate (150mg, 0.324 mmol) and 3-aminopropionitrile, by the same procedure as inExample 11.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.72 (2H, t, J=6.4 Hz), 3.41 (2H, m),4.03 (3H, s), 6.54 (1H, d, J=5.2 Hz), 7.25 (1H, dd, J=2.8, 8.8 Hz), 7.37(1H, t, J=6.0 Hz), 7.50 (1H, d, J=2.8 Hz), 7.52 (1H, s), 7.74 (1H, s),7.86 (1H, s), 8.24 (1H, d, J=8.8 Hz), 8.31 (1H, s), 8.66 (1H, s), 8.67(1H, d, J=5.2 Hz).

Example 5894-(3-Chloro-4-(cis-2-fluoro-cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (39.0 mg, 0.088 mmol, 27%) was obtained as whitecrystals from phenylN-(4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2-chlorophenyl)carbamate (150mg, 0.324 mmol) and cis-2-fluorocyclopropylamine tosylate, by the sameprocedure as in Example 11.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.82 (1H, m), 1.11 (1H, m), 2.68 (1H,m), 4.04 (3H, s), 4.78 (1H, m), 6.54 (1H, d, J=5.2 Hz), 7.25 (1H, dd,J=2.8, 8.8 Hz), 7.32 (1H, d, J=3.6 Hz), 7.50 (1H, d, J=2.8 Hz), 7.52(1H, s), 7.74 (1H, s), 7.86 (1H, s), 8.25 (1H, s), 8.29 (1H, d, J=8.8Hz), 8.66 (1H, s), 8.67 (1H, d, J=5.2 Hz).

Example 5904-(3-Chloro-4-(aminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (61.0 mg, 79%) was obtained as light red crystalsfrom phenylN-(4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2-chlorophenyl)carbamate (100mg, 0.22 mmol) and ammonia water (2 ml), by the same procedure as inExample 11.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 4.01 (3H, s), 6.41 (2H, s), 6.51 (1H,d, J=5.2 Hz), 7.21 (1H, d, J=9.2 Hz), 7.47 (1H, d, J=2.8 Hz), 7.50 (1H,s), 7.73 (1H, s), 7.84 (1H, s), 8.15 (1H, s), 8.25 (1H, d, J=8.8 Hz),8.65 (1H, d, J=5.2 Hz), 8.66 (1H, s).

Example 591N-(4-(6,7-Dimethoxyquinolin-4-yloxy)phenyl)-N′-thiazol-2-ylurea

4-(6,7-Dimethoxyquinolin-4-yloxy)phenylcarbamic acid phenyl ester (208mg, 0.500 mmol) and 2-aminothiazole (100 mg, 1.00 mmol) were heated andstirred in dimethylsulfoxide (1 ml) at 85° C. for 1 hour. The reactionsolution was distributed between ethyl acetate and water, the organiclayer was washed with 1N aqueous sodium hydroxide, water and saturatedbrine and dried over anhydrous magnesium sulfate, the drying agent wasfiltered off and the filtrate was distilled off under reduced pressure.The obtained crude product was subjected to silica gel columnchromatography (eluent—ethyl acetate:methanol=20:1), the fractioncontaining the target substance was concentrated and suspended in ethylacetate, the suspension was diluted with hexane and the crystals werefiltered out, washed with hexane and blow-dried to obtain the titlecompound (150 mg, 0.355 mmol, 71%) as colorless crystals.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 4.02-4.05 (6H, m), 6.46 (1H, d, J=5.2Hz), 6.92 (1H, d, J=3.6 Hz), 7.16-7.22 (2H, m), 7.40-7.44 (2H, m), 7.56(1H, s), 7.61-7.67 (2H, m), 8.48 (1H, d, J=5.2 Hz).

The intermediate was synthesized in the following manner.

Production Example 591-1 4-(6,7-Dimethoxyquinolin-4-yloxy)phenylcarbamicacid phenyl ester

The 4-(6,7-dimethoxyquinolin-4-yloxy)phenylamine (2.96 g, 10.0 mmol)obtained by the method described in WO97/17329 and triethylamine (1.21g, 12.0 mmol) were dissolved in dimethylformamide (30 ml), and afteradding phenyl chloroformate (1.72 g, 11.0 mmol) while cooling on ice,the mixture was stirred at room temperature for 1 hour. The reactionsolution was distributed between ethyl acetate and water, the organiclayer was washed with water and saturated brine and dried over anhydrousmagnesium sulfate, the drying agent was filtered off and the filtratewas distilled off under reduced pressure. The obtained crude product wassubjected to silica gel column chromatography (eluent—ethylacetate:hexane=3:1), the fraction containing the target substance wasconcentrated and suspended in ethyl acetate, the suspension was dilutedwith hexane and the crystals were filtered out, washed with hexane andblow-dried to obtain the title compound (2.50 g, 6.00 mmol, 60%) ascolorless crystals.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 4.05 (3H, s), 4.06 (3H, s), 6.46 (1H,d, J=5.2 Hz), 7.12 (1H, br s), 7.16-7.28 (5H, m), 7.38-7.44 (3H, m),7.53-7.60 (3H, m), 8.49 (1H, d, J=5.2 Hz).

Example 592N-Cyclopropyl-N′-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)urea

4-(6,7-Dimethoxyquinolin-4-yloxy)phenylcarbamic acid phenyl ester (104mg, 0.250 mmol) and cyclopropylamine (28.5 mg, 0.500 mmol) were stirredin dimethylsulfoxide (1 ml) at room temperature for 2 hours. Thereaction solution was distributed between ethyl acetate and water, theorganic layer was washed with 1N aqueous sodium hydroxide, water andsaturated brine and dried over anhydrous magnesium sulfate, the dryingagent was filtered off and the filtrate was distilled off under reducedpressure. The obtained crude product was subjected to silica gel columnchromatography (eluent—ethyl acetate:methanol=15:1), the fractioncontaining the target substance was concentrated and suspended in ethylacetate, the suspension was diluted with hexane and the crystals werefiltered out, washed with hexane and blow-dried to obtain the titlecompound (76 mg, 0.200 mmol, 80%) as colorless crystals.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 0.70-0.75 (2H, m), 0.87-0.92 (2H, m),2.60-2.66 (1H, m), 4.04-4.07 (6H, m), 4.93 (1H, s), 6.45 (1H, d, J=5.2Hz), 6.99 (1H, s), 7.12-7.18 (2H, m), 7.42 (1H, s), 7.50-7.56 (2H, m),7.57 (1H, s), 8.48 (1H, d, J=5.2 Hz).

Example 593N-(4-(6,7-Dimethoxyquinolin-4-yloxy)-2-fluorophenyl)-N′-thiazol-2-ylurea

4-(6,7-Dimethoxyquinolin-4-yloxy)-2-fluorophenylcarbamic acid phenylester (109 mg, 0.250 mmol) and 2-aminothiazole (50.0 mg, 0.500 mmol)were heated and stirred in dimethylsulfoxide (1 ml) at 85° C. for 2hours. The reaction solution was distributed between ethyl acetate andwater, the organic layer was washed with 1N aqueous sodium hydroxide,water and saturated brine and dried over anhydrous magnesium sulfate,the drying agent was filtered off and the filtrate was distilled offunder reduced pressure. The obtained crude product was subjected tosilica gel column chromatography (eluent—ethyl acetate:methanol=30:1),the fraction containing the target substance was concentrated andsuspended in ethyl acetate, the suspension was diluted with hexane andthe crystals were filtered out, washed with hexane and blow-dried toobtain the title compound (95.0 mg, 0.216 mmol, 86%) as colorlesscrystals.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 4.05 (3H, s), 4.06 (3H, s), 6.52 (1H,d, J=5.2 Hz), 6.92 (1H, d, J=3.6 Hz), 6.96-7.04 (2H, m), 7.36 (1H, d,J=3.6 Hz), 7.40 (1H, s), 7.53 (1H, s), 8.30-8.36 (1H, m), 8.47 (1H, d,J=5.2 Hz).

The intermediate was synthesized in the following manner.

Production Example 593-14-(6,7-Dimethoxyquinolin-4-yloxy)-2-fluorophenylcarbamic acid phenylester

4-(6,7-Dimethoxyquinolin-4-yloxy)-2-fluorophenylamine (3.55 g, 9.17mmol) obtained by the method described in Japanese Unexamined PatentPublication HEI No. 11-158149 and pyridine (3.63 g, 45.8 mmol) weredissolved in dimethylformamide (30 ml), and after adding phenylchloroformate (1.51 g, 9.64 mmol) while cooling on ice, the mixture wasstirred at room temperature for 1 hour. The reaction solution wasdistributed between ethyl acetate and water, the organic layer waswashed with water and saturated brine and dried over anhydrous magnesiumsulfate, the drying agent was filtered off and the filtrate wasdistilled off under reduced pressure. The obtained crude product wassubjected to silica gel column chromatography (eluent—ethylacetate:hexane=2:1), the fraction containing the target substance wasconcentrated and suspended in ethyl acetate, the suspension was dilutedwith hexane and the crystals were filtered out, washed with hexane andblow-dried to obtain the title compound (2.30 g, 5.29 mmol, 58%) ascolorless crystals.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 4.05 (3H, s), 4.06 (3H, s), 6.52 (1H,d, J=5.2 Hz), 7.00-7.05 (2H, m), 7.18-7.30 (4H, m), 7.40-7.46 (3H, m),7.50 (1H, s), 8.21 (1H, br s), 8.53 (1H, d, J=5.2 Hz).

Example 594N-Cyclopropyl-N′-(4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl)urea

4-(6,7-Dimethoxyquinolin-4-yloxy)-2-fluorophenylcarbamic acid phenylester (109 mg, 0.250 mmol) and cyclopropylamine (28.5 mg, 0.500 mmol)were stirred in dimethylsulfoxide (1 ml) at room temperature for 2hours. The reaction solution was distributed between ethyl acetate andwater, the organic layer was washed with 1N aqueous sodium hydroxide,water and saturated brine and dried over anhydrous magnesium sulfate,the drying agent was filtered off and the filtrate was distilled offunder reduced pressure. The obtained crude product was subjected tosilica gel column chromatography (eluent—ethyl acetate:methanol=50:1),the fraction containing the target substance was concentrated andsuspended in ethyl acetate, the suspension was diluted with hexane andthe crystals were filtered out, washed with hexane and blow-dried toobtain the title compound (73 mg, 0.183 mmol, 73%) as colorlesscrystals.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 0.71-0.76 (2H, m), 0.90-0.95 (2H, m),2.60-2.66 (1H, m), 4.05 (3H, s), 4.06 (3H, s), 5.00 (1H, s), 6.50 (1H,d, J=5.2 Hz), 6.95-7.02 (2H, m), 7.23 (1H, s), 7.43 (1H, s), 7.52 (1H,s), 8.25-8.32 (1H, m), 8.51 (1H, d, J=5.2 Hz).

Example 5954-(3-Chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-(2-ethoxyethoxy)-6-quinolinecarboxamide

The title compound (96.0 mg, 0.198 mmol, 39.7%) was obtained as lightyellow crystals from4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-hydroxy-6-quinolinecarboxamide(206 mg, 0.499 mmol) and 2-ethoxyethylbromide, by the same procedure asin Example 7.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.42 (2H, m), 0.65 (2H, m), 1.16 (3H,t, J=7.2 Hz), 2.56 (1H, m), 3.53 (2H, q, J=7.2 Hz), 3.83 (2H, m), 4.40(2H, m), 6.51 (1H, d, J=5.2 Hz), 7.18 (1H, d, J=2.8 Hz), 7.24 (1H, dd,J=2.8, 9.2 Hz), 7.49 (1H, d, J=2.8 Hz), 7.56 (1H, s), 7.85 (1H, s), 7.87(1H, s), 7.97 (1H, s), 8.26 (1H, d, J=9.2 Hz), 8.66 (1H, d, J=5.2 Hz),8.78 (1H, s).

Example 5964-(3-Chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-cyclopropylmethoxy-6-quinolinecarboxamide

The title compound (61.4 mg, 0.132 mmol, 26.4%) was obtained as lightyellow crystals from4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-hydroxy-6-quinolinecarboxamide(206 mg, 0.499 mmol) and bromomethylcyclopropane, by the same procedureas in Example 7.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.41-0.47 (4H, m), 0.60-0.69 (4H, m),1.39 (1H, m), 2.56 (1H, m), 4.14 (2H, d, J=6.8 Hz), 6.52 (1H, d, J=5.2Hz), 7.20 (1H, d, J=2.8 Hz), 7.25 (1H, dd, J=2.8, 8.8 Hz), 7.49-7.50(2H, m), 7.83 (1H, s), 7.85 (1H, s), 7.98 (1H, s), 8.28 (1H, d, J=8.8Hz), 8.66 (1H, d, J=5.2 Hz), 8.72 (1H, s).

Example 5974-(3-Fluoro-4-(methylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (37 mg) was obtained as yellow crystals from phenylN-(4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2-fluorophenyl)carbamate (73mg) and methylamine (2M tetrahydrofuran solution), by the same procedureas in Example 11.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.65 (3H, d, J=4.4 Hz), 4.01 (3H, s),6.45-6.46 (1H, m), 6.51-6.52 (1H, m), 7.04-7.06 (1H, m), 7.28-7.31 (1H,m), 7.50 (1H, s), 7.72 (1H, s), 7.84 (1H, s), 8.17-8.22 (1H, m), 8.40(1H, s), 8.64-8.65 (2H, m).

Example 5984-(3-Fluoro-4-(ethylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (38 mg) was obtained as yellow crystals from phenylN-(4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2-fluorophenyl)carbamate (69mg) and ethylamine (2M tetrahydrofuran solution), by the same procedureas in Example 11.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.05 (3H, t, J=7 Hz), 3.11 (2H, q,J=7 Hz), 4.01 (3H, s), 6.50-6.52 (1H, m), 6.57-6.58 (1H, m), 7.04-7.06(1H, m), 7.28-7.32 (1H, m), 7.50 (1H, s), 7.73 (1H, s), 7.84 (1H, s),8.19-8.24 (1H, m), 8.33 (1H, s), 8.64-8.65 (2H, m).

Example 599 tert-Butyl4-((((4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolyl)carbonyl)amino)methyl)-1-piperidinecarboxylate

4-(3-Chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid) (171 mg, 0.40 mmol) was dissolved in dimethylformamide (4 ml)under a nitrogen atmosphere, and then tert-butyl4-aminomethyl-1-piperidinecarboxylate (171 mg, 0.80 mmol), triethylamine(0.2 ml) and1H-1,2,3-benzotriazol-1-yloxy)(tri(dimethylamino))phosphoniumhexafluorophosphate (265 mg, 0.60 mmol) were added in that order at roomtemperature, and the mixture was stirred overnight. The reactionsolution was distributed between ethyl acetate and water, and theorganic layer was washed with water and saturated brine and dried overanhydrous sodium sulfate. The solvent was distilled off, the residue wassuspended in ethyl acetate and diluted with hexane, and the crystalswere filtered out and blow-dried to obtain the title compound (249 mg,quantitative) as white crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.41 (2H, m), 0.65 (2H, m), 1.05 (2H,m), 1.22 (1H, m), 1.37 (9H, s), 1.66 (2H, m), 2.56 (1H, m), 2.67 (2H,m), 3.20 (2H, m), 3.93 (2H, m), 3.99 (3H, s), 6.51 (1H, d, J=5.2 Hz),7.17-7.24 (2H, m), 7.46 (1H, d, J=2.8 Hz), 7.49 (1H, s), 7.97 (1H, s),8.26 (1H, dd, J=2.8, 8.8 Hz), 8.39 (1H, m), 8.46 (1H, s), 8.64 (1H, d,J=5.2 Hz).

Example 600N6-(1-Methyl-4-piperidylmethyl)-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

After adding trifluoroacetic acid (1 ml) to tert-butyl4-((((4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolyl)carbonyl)amino)methyl)-1-piperidinecarboxylate(249 mg, 0.40 mmol) at room temperature, the mixture was stirred for 2hours. The reaction solution was poured into saturated aqueous sodiumbicarbonate for neutralization and extracted 3 times with ethyl acetate,and the organic layer was dried over anhydrous sodium sulfate. Afterdistilling off the solvent, the residue was dissolved in tetrahydrofuran(5 ml)—methanol (5 ml), and then 37% aqueous formaldehyde (0.5 ml),acetic acid (0.05 ml) and sodium cyanoborohydride (50 mg, 0.8 mmol) wereadded in that order at room temperature and the mixture was stirred for1 hour. The reaction solution was distributed between ethyl acetate andsaturated aqueous sodium bicarbonate, and the organic layer was washedwith saturated aqueous sodium bicarbonate and saturated brine and driedover anhydrous sodium sulfate. After distilling off the solvent, ethylacetate was used for crystallization and the crystals were filtered outand blow-dried to obtain the title compound (125.6 mg, 0.233 mmol,58.4%) as white crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.42 (2H, m), 0.65 (2H, m), 1.18 (2H,m), 1.49 (1H, m), 1.64 (2H, m), 1.78 (2H, m), 2.11 (3H, s), 2.56 (1H,m), 2.73 (2H, m), 3.18 (2H, m), 3.99 (3H, s), 6.51 (1H, d, J=5.2 Hz),7.18 (1H, d, J=2.4 Hz), 7.22 (1H, dd, J=2.8, 8.8 Hz), 7.46 (1H, d, J=2.4Hz), 7.49 (1H, s), 7.97 (1H, s), 8.26 (1H, dd, J=2.8, 8.8 Hz), 8.35 (1H,m), 8.47 (1H, s), 8.64 (1H, d, J=5.2 Hz).

Example 601 tert-Butyl4-(((4-(3-chloro-4-((cyclopropylamino)carbonyl)amino)phenoxy)-6-(methylaminocarbonyl)-7-quinolyl)oxy)methyl)-1-piperidinecarboxylate

The title compound (188.4 mg, 0.302 mmol, 57.1%) was obtained as whitecrystals fromN6-methyl-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-hydroxy-6-quinolinecarboxamide(225.5 mg, 0.528 mmol) and tert-butyl4-(bromomethyl)-1-piperidinecarboxylate, by the same procedure as inExample 7.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.41 (2H, m), 0.65 (2H, m), 1.13-1.26(3H, m), 1.39 (9H, s), 1.75 (2H, m), 2.06 (1H, m), 2.56 (1H, m), 2.75(1H, m), 2.81 (3H, d, J=4.8 Hz), 3.99 (2H, m), 4.10 (2H, m), 6.51 (1H,d, J=5.2 Hz), 7.18 (1H, d, J=2.8 Hz), 7.21 (1H, dd, J=2.8, 9.2 Hz), 7.45(1H, d, J=2.8 Hz), 7.48 (1H, s), 7.96 (1H, s), 8.18 (1H, d, J=4.8 Hz),8.25 (1H, d, J=9.2 Hz), 8.43 (1H, s), 8.64 (1H, d, J=5.2 Hz).

Example 602 tert-Butyl4-(((4-(3-chloro-4-((cyclopropylamino)carbonyl)amino)phenoxy)-6-(ethylaminocarbonyl)-7-quinolyl)oxy)methyl)-1-piperidinecarboxylate

The title compound (155.4 mg, 0.244 mmol, 63.0%) was obtained as lightyellow crystals fromN6-ethyl-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-hydroxy-6-quinolinecarboxamide)(170.5 mg, 0.387 mmol) and tert-butyl4-(bromomethyl)-1-piperidinecarboxylate, by the same procedure as inExample 7.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.41 (2H, m), 0.65 (2H, m), 1.10-1.16(4H, m), 1.27 (2H, m), 1.39 (9H, s), 1.76 (2H, m), 2.05 (1H, m), 2.56(1H, m), 2.75 (1H, m), 3.20-3.40 (2H, m), 4.01 (2H, m), 4.11 (2H, m),6.51 (1H, d, J=5.2 Hz), 7.17-7.23 (2H, m), 7.45 (1H, d, J=2.8 Hz), 7.48(1H, s), 7.96 (1H, s), 8.20-8.27 (2H, m), 8.44 (1H, s), 8.64 (1H, d,J=5.2 Hz).

Example 603N6-Methyl-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-((1-methyl-4-piperidyl)methoxy)-6-quinolinecarboxamide

After adding trifluoroacetic acid (1 ml) to tert-butyl4-(((4-(3-chloro-4-((cyclopropylamino)carbonyl)amino)phenoxy)-6-(methylaminocarbonyl)-7-quinolyl)oxy)methyl)-1-piperidinecarboxylate(179.0 mg, 0.287 mmol) at room temperature, the mixture was stirred for2 hours. The reaction solution was poured into saturated aqueous sodiumbicarbonate for neutralization and extracted 5 times with ethylacetate-tetrahydrofuran (1:1), and the organic layer was dried overanhydrous sodium sulfate. After distilling off the solvent, the residuewas dissolved in tetrahydrofuran (5 ml)—methanol (5 ml), and then 37%aqueous formaldehyde (0.3 ml), acetic acid (0.05 ml) and sodiumcyanoborohydride (36 mg, 0.57 mmol) were added in that order at roomtemperature and the mixture was stirred for 1 hour. The reactionsolution was distributed between ethyl acetate and saturated aqueoussodium bicarbonate, and the organic layer was washed with saturatedaqueous sodium bicarbonate and saturated brine and dried over anhydroussodium sulfate. After distilling off the solvent, ethyl acetate was usedfor crystallization and the crystals were filtered out and blow-dried toobtain the title compound (101.0 mg, 0.188 mmol, 65.4%) as whitecrystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.41 (2H, m), 0.65 (2H, m), 1.34 (2H,m), 1.72-1.89 (5H, m), 2.14 (3H, s), 2.56 (1H, m), 2.78 (2H, m), 2.82(3H, d, J=4.4 Hz), 4.08 (2H, d, J=6.4 Hz), 6.51 (1H, d, J=5.2 Hz),7.19-7.23 (2H, m), 7.45 (1H, d, J=2.8 Hz), 7.48 (1H, s), 7.97 (1H, s),8.20 (1H, d, J=4.4 Hz), 8.25 (1H, d, J=9.2 Hz), 8.45 (1H, s), 8.63 (1H,d, J=5.2 Hz).

Example 604N6-Ethyl-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-((1-methyl-4-piperidyl)methoxy)-6-quinolinecarboxamide

The title compound (82.6 mg, 0.150 mmol, 64.8%) was obtained as lightyellow crystals from tert-butyl4-(((4-(3-chloro-4-((cyclopropylamino)carbonyl)amino)phenoxy)-6-(ethylaminocarbonyl)-7-quinolyl)oxy)methyl)-1-piperidinecarboxylate(147.2 mg, 0.231 mmol), by the same procedure as in Example 603.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.42 (2H, m), 0.65 (2H, m), 1.14 (3H,t, J=7.2 Hz), 1.36 (2H, m), 1.75-1.89 (5H, m), 2.15 (3H, s), 2.56 (1H,m), 2.79 (2H, m), 3.20-3.40 (2H, m), 4.08 (2H, d, J=6.4 Hz), 6.51 (1H,d, J=5.2 Hz), 7.20-7.23 (2H, m), 7.46 (1H, d, J=2.8 Hz), 7.48 (1H, s),7.98 (1H, s), 8.22-8.27 (2H, m), 8.47 (1H, s), 8.64 (1H, d, J=5.2 Hz).

Example 6051-[4-(7-Benzyloxy-6-cyanoquinolin-4-yloxy)-2-chloro-phenyl]-3-ethyl-urea

A carbamate (1.51 g) was obtained as a solid from4-(4-amino-3-chlorophenoxy)-7-benzyloxy-quinoline-6-carbonitrile (1.78g) and phenyl chlorocarbonate, by the same procedure as in ProductionExample 17. The carbamate (1.5 g) was then treated with ethylamine indimethylsulfoxide at room temperature in the same manner as Example 11,to obtain the title compound (1.4 g) as a solid.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.06 (3H, t, J=7.6 Hz), 3.08-3.16(2H, m), 5.45 (2H, s), 6.58 (1H, d, J=5.2 Hz), 6.99 (1H, t, J=5.2 Hz),7.23 (1H, dd, J=2.8 Hz, J=9.2 Hz), 7.36 (1H, t, J=7.2 Hz), 7.44 (2H, t,J=7.2 Hz), 7.48 (1H, d, J=2.8 Hz), 7.54 (2H, d, J=7.2 Hz), 7.70 (1H, s),8.06 (1H, s), 8.26 (1H, d, J=8.8 Hz), 8.72 (1H, d, J=5.2 Hz), 8.76 (1H,s).

Example 6061-(2-Chloro-4-(6-cyano-(2R)-7-oxiranylmethoxyquinolin-4-yloxy)-phenyl)-3-ethylurea

1-(4-(7-Benzyloxy-6-cyanoquinolin-4-yloxy)-2-chloro-phenyl)-3-ethylurea(1 g) was treated with trifluoroacetic acid and thioanisole fordeprotection in the same manner as Production Example 21, and theobtained hydroxy compound (0.48 g) was treated in the same manner asExample 543 to obtain the title compound (0.31 g) as a solid.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.06 (3H, t, J=7.2 Hz), 2.81 (1H, dd,J=2.8 Hz, J=5.2 Hz), 2.91 (1H, t, J=4.8 Hz), 3.80-3.16 (2H, m),3.44-3.48 (1H, m), 4.17 (1H, dd, J=6.4 Hz, J=11.6 Hz), 4.71 (1H, dd, J=2Hz, J=11.6 Hz), 6.59 (1H, d, J=5.2 Hz), 6.99 (1H, t, J=5.2 Hz), 7.24(1H, dd, J=2.8 Hz, J=9.2 Hz), 7.49 (1H, d, J=2.8 Hz), 7.64 (1H, s), 8.07(1H, s), 8.27 (1H, d, J=9.2 Hz), 8.73 (1H, d, J=5.2 Hz), 8.76 (1H, s).

Example 6071-(2-Chloro-4-(6-cyano-7-((2R)-2-hydroxy-3-pyrrolidin-1-ylpropoxy)quinolin-4-yloxy)phenyl)-3-ethylurea

The title compound (38 mg) was obtained as a solid from1-(2-chloro-4-(6-cyano-(2R)-7-oxiranylmethoxyquinolin-4-yloxy)-phenyl)-3-ethylurea(110 mg) and pyrrolidine, in the same manner as Example 544.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.07 (3H, t, J=7.2 Hz), 1.62-1.72(4H, m), 2.44-2.56 (5H, m), 2.67-2.73 (1H, m), 3.08-3.16 (2H, m),3.97-4.04 (1H, m), 4.17-4.23 (1H, m), 4.25-4.32 (1H, m), 5.02 (1H, d,J=4.4 Hz), 6.57 (1H, d, J=5.2 Hz), 6.97-7.03 (1H, m), 7.23 (1H, dd,J=2.4 Hz, J=9.2 Hz), 7.49 (1H, d, J=2.4 Hz), 7.61 (1H, s), 8.07 (1H, s),8.27 (1H, d, J=9.2 Hz), 8.72 (1H, d, J=5.2 Hz), 8.73 (1H, s).

Example 6081-(2-Chloro-4-(6-cyano-7-((2R)-3-diethylamino-2-hydroxypropoxy)quinolin-4-yloxy)phenyl)-3-ethylurea

The title compound (12 mg) was obtained as a solid from1-(2-chloro-4-(6-cyano-(2R)-7-oxiranylmethoxyquinolin-4-yloxy)phenyl)-3-ethylurea(100 mg) and diethylamine, in the same manner as Example 544.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.96 (6H, t, J=7.2 Hz), 1.06 (3H, t,J=7.2 Hz), 2.42-2.57 (5H, m), 2.64 (1H, dd, J=7.6 Hz, J=13.2 Hz),3.08-3.16 (2H, m), 3.91-4.00 (1H, m), 4.21 (1H, dd, J=5.2 Hz, J=10 Hz),4.30 (1H, dd, J=3.6 Hz, J=10 Hz), 4.88-4.93 (1H, m), 6.57 (1H, d, J=5.2Hz), 6.99 (1H, t, J=4.8 Hz), 7.23 (1H, dd, J=2.8 Hz, J=9.2 Hz), 7.49(1H, d, J=2.8 Hz), 7.61 (1H, s), 8.06 (1H, s), 8.26 (1H, d, J=9.2 Hz),8.72 (1H, d, J=5.2 Hz), 8.73 (1H, s).

Example 6091-(2-Chloro-4-(6-cyano-7-((2R)-2-hydroxy-3-piperidin-1-ylpropoxy)quinolin-4-yloxy)phenyl)-3-ethylurea

The title compound (46 mg) was obtained as a solid from1-(2-chloro-4-(6-cyano-(2R)-7-oxiranylmethoxyquinolin-4-yloxy)phenyl)-3-ethylurea(100 mg) and piperidine, in the same manner as Example 544.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.06 (3H, t, J=7.2 Hz), 1.32-1.39(2H, m), 1.44-1.53 (4H, m), 2.34-2.51 (6H, m), 3.08-3.16 (2H, m),3.99-4.07 (1H, m), 4.19 (1H, dd, J=5.6 Hz, J=10.4 Hz), 4.30 (1H, dd,J=3.2 Hz, J=10.4 Hz), 4.93 (1H, d, J=4.4 Hz), 6.57 (1H, d, J=5.2 Hz),6.99 (1H, t, J=5.2 Hz), 7.23 (1H, dd, J=2.8 Hz, J=9.2 Hz), 7.48 (1H, d,J=2.8 Hz), 7.62 (1H, s), 8.06 (1H, s), 8.27 (1H, d, J=9.2 Hz), 8.72 (1H,d, J=5.2 Hz), 8.72 (1H, s).

Example 6101-(2-Chloro-4-(6-(4-(piperidin-4-ylmethoxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy}phenyl)-3-cyclopropylurea

After dissolving 37 mg of4-(4-(4-(3-chloro-4-(3-cyclopropylureido)phenoxy)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenoxymethyl)piperidine-1-carboxylicacid tert-butyl ester in 1 ml of trifluoroacetic acid, the mixture wasstirred at room temperature for 2 hours. The reaction system wasconcentrated under reduced pressure, saturated sodium bicarbonate waterwas added to alkalinity and liquid separation and extraction wereperformed with ethyl acetate. The organic layer was dried over sodiumsulfate and concentrated to dryness to obtain the 25 mg of the titlecompound.

MS Spectrum (ESI): 533 (M+1),

Example 6111-(2-Chloro-4-{6-(4-(1-methylpiperidin-4-ylmethoxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy}phenyl)-3-cyclopropylurea

After adding 2 ml of methanol, 2 ml of methylene chloride, 0.05 ml of37% aqueous formaldehyde and 4.4 μl of acetic acid to 24 mg of1-(2-chloro-4-{6-[4-(piperidin-4-ylmethoxy)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy}-2-phenyl)-3-cyclopropylurea,30 mg of sodium triacetoxyborohydride was added while stirring, whichwas continued at room temperature for 40 minutes. Water was added,extraction was performed with an ethyl acetate-tetrahydrofuran (5:1)mixed solvent, and the extract was concentrated and subjected to NHsilica gel column chromatography to obtain 12 mg of the title compound.

MS Spectrum (ESI): 547 (M+1),

Example 6124-{4-[4-[3-Chloro-4-(3-cyclopropylureido)phenoxy]-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenoxymethyl}piperidine-1-carboxylicacid tert-butyl ester

After adding 38 mg of 4-bromomethylpiperidine-1-carboxylic acidtert-butyl ester, 59 mg of potassium carbonate and 1 ml ofdimethylformamide to 60 mg of1-{2-chloro-4-[6-(4-hydroxyphenyl)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]-2-phenyl}-3-cyclopropylurea,the mixture was stirred at 70-75° C. for 6 hours. It was then returnedto room temperature, water was added, and liquid separation andextraction were performed with ethyl acetate. The organic layer wasdried over sodium sulfate and concentrated to dryness to obtain 63 mg ofthe title compound.

MS Spectrum (ESI): 786 (M+23),

Example 6134-(2,3-Dimethyl-4-(methylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (30 mg) was obtained as colorless crystals fromphenylN-(4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2,3-dimethylphenyl)carbamate)(56 mg) and methylamine (2M tetrahydrofuran solution), by the sameprocedure as in Example 11.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.01 (3H, s), 2.14 (3H, s), 2.64 (3H,d, J=3.2 Hz), 4.01 (3H, s), 6.24 (1H, d, J=5.2 Hz), 6.28 (1H, d, J=4.4Hz), 6.97 (1H, d, J=8.8 Hz), 7.49 (1H, s), 7.60 (1H, d, J=8.4 Hz),7.73-7.85 (3H, m), 8.59 (1H, d, J=4.8 Hz), 8.71 (1H, s).

Example 6144-(2,3-Dimethyl-4-(ethylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (33 mg) was obtained as colorless crystals fromphenylN-(4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2,3-dimethylphenyl)carbamate(55 mg) and ethylamine (2M tetrahydrofuran solution), by the sameprocedure as in Example 11.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.54 (3H, t, J=7 Hz), 2.01 (3H, s),2.14 (3H, s), 3.07-3.12 (2H, m), 4.01 (3H, s), 6.24 (1H, d, J=4.8 Hz),6.41 (1H, m), 6.97 (1H, d, J=8.4 Hz), 7.49 (1H, s), 7.64 (1H, d, J=8.8Hz), 7.73 (2H, brs), 7.85 (1H, s), 8.59 (1H, d, J=5.2 Hz), 8.71 (1H, s).

Example 6154-(3-Chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-((2R)-2-hydroxy-3-(1-pyrrolidino)propoxy)-6-quinolinecarboxamide

After adding (2R)oxiran-2-ylmethyl 4-methyl-1-benzenesulfonate (308 mg,1.35 mmol), potassium carbonate (149 mg, 1.08 mmol) anddimethylformamide (9 ml) to4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-hydroxy-6-quinolinecarboxamide(372.0 mg, 0.90 mmol), the mixture was stirred at 60° C. for 7 hours.The reaction solution was allowed to stand to return to roomtemperature, and then pyrrolidine (1 ml) was added and the mixture wasstirred overnight. The reaction solution was distributed between ethylacetate and water, and the organic layer was washed with water andsaturated brine and then dried over anhydrous sodium sulfate. Thesolvent was distilled off, the residue was subjected to silica gelcolumn chromatography (eluent—ethyl acetate:methanol=95:5), the fractioncontaining the target substance was concentrated, and crystals wereprecipitated from ethyl acetate, filtered out and blow-dried to obtainthe title compound (133.3 mg, 0.247 mmol, 27.4%) as white crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.42 (2H, m), 0.65 (2H, m), 1.67 (4H,m), 2.45-2.59 (6H, m), 2.69 (1H, m), 4.05 (1H, m), 4.19 (1H, dd, J=6.0,10.0 Hz), 4.32 (1H, dd, J=3.6, 10.0 Hz), 5.19 (1H, d, J=4.8 Hz), 6.51(1H, d, J=5.2 Hz), 7.18 (1H, d, J=2.8 Hz), 7.24 (1H, dd, J=2.8, 8.8 Hz),7.49 (1H, d, J=2.8 Hz), 7.53 (1H, s), 7.82 (1H, s), 7.97 (1H, s), 7.99(1H, s), 8.26 (1H, d, J=8.8 Hz), 8.66 (1H, d, J=5.2 Hz), 8.80 (1H, s).

Example 616N-{[4-(6-Carbamoyl-7-methoxy-4-quinolyl)oxy]-2-methylphenyl}-N′-(4-fluorophenyl)-N-methylurea

After dissolving 6-carbamoyl-4-chloro-7-methoxyquinoline (100 mg, 0.2982mmol), N-(4-fluorophenyl)-N′-(4-hydroxy-2-methylphenyl)-N′-methylurea(100 mg, 0.2917 mmol) and diisopropylethylamine (0.1 ml, 0.4375 mmol) inN-methylpyrrolidone (0.1 ml), the mixture was heated and stirred at 150°C. for 3 hours. After cooling to room temperature, water was added tothe reaction solution, the mixture was extracted with ethyl acetate, theextract was washed with saturated brine and dried over anhydrousmagnesium sulfate, and the solvent was distilled off under reducedpressure. The residue was purified by silica gel column chromatography(hexane-ethyl acetate-ethanol) and then by NH silica gel columnchromatography (hexane-ethyl acetate-ethanol), after which diethyl etherwas added to the obtained amorphous substance to make a suspension, thesuspension was diluted with hexane, and the precipitate was filteredout, washed with diethyl ether:hexane=1:1 and dried by aspiration toobtain the title compound (11 mg, 0.023 mmol, 7.95%) as light yellowcrystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.21 (3H, s), 3.16 (3H, s), 4.02 (3H,s), 6.71 (1H, d, J=5.2 Hz), 7.05 (2H, t, J=8.8 Hz), 7.18 (1H, dd, J=2.8Hz, 8.4 Hz), 7.28 (1H, d, J=2.8 Hz), 7.39-7.44 (3H, m), 7.51 (1H, s),7.72 (1H, brs), 7.84 (1H, brs), 7.89 (1H, brs), 8.66 (1H, s), 8.70 (1H,d, J=5.2 Hz).

The starting materials were synthesized in the following manner.

Production Example 616-1 4-Benzyloxy-2-methylaniline

After dissolving 4-amino-3-cresol (10 g, 81.20 mmol) indimethylsulfoxide (80 ml), sodium hydride (3.25 g, 81.20 mmol, 60% inoil) was added and the mixture was stirred for 15 minutes at roomtemperature under a nitrogen atmosphere. Benzyl bromide (4.83 ml, 40.60mmol) was added, and the mixture was stirred overnight at roomtemperature under a nitrogen atmosphere. Water was added to the reactionsolution, extraction was performed with diethyl ether/tetrahydrofuran,the extract was washed with saturated brine and dried over anhydrousmagnesium sulfate, and the solvent was distilled off under reducedpressure. The residue was adsorbed onto silica gel, purified by silicagel column chromatography (hexane-ethyl acetate-ethanol) and then by NHsilica gel column chromatography (hexane-ethyl acetate) to obtain thetitle compound (6.55 g, 30.72 mmol, 75.64%) as a violet oil.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 2.16 (3H, s), 3.36 (2H, brs), 4.99 (2H,s), 6.61 (1H, d, J=8.4 Hz), 6.69 (1H, dd, J=2.8 Hz, 8.4 Hz), 6.75 (1H,d, J=2.8 Hz), 7.30 (1H, t, J=6.8 Hz), 7.37 (2H, t, J=6.8 Hz), 7.42 (2H,d, J=6.8 Hz).

Production Example 616-2 N-Methyl-4-benzyloxy-2-methylaniline

After dissolving 4-benzyloxy-2-methylaniline (6.55 g, 30.72 mmol) inN,N-dimethylformamide (10 ml) and methanol (60 ml),1H-benzotriazole-1-methanol (4.58 g, 30.72 mmol) was added and themixture was stirred for 30 minutes at room temperature.N,N-Dimethylformamide (20 ml) was added for complete dissolution of theprecipitated crystals, sodium borohydride (2.32 g, 61.44 mmol) was addedin small portions at a time at room temperature (internal temperatureincrease), and the mixture was stirred for 30 minutes. Water was addedto the reaction solution, extraction was performed ethyl acetate, theextract was washed with saturated brine and dried over anhydrousmagnesium sulfate, and the solvent was distilled off under reducedpressure. The residue was adsorbed onto silica gel and purified bysilica gel column chromatography (hexane-ethyl acetate) to obtain thetitle compound (4.364 g, 19.20 mmol, 62.49%) as a brown oil.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 2.13 (3H, s), 2.86 (3H, s), 4.99 (2H,s), 6.24 (1H, d, J=9.6 Hz), 6.79-6.81 (2H, m), 7.30 (1H, t, J=6.8 Hz),7.37 (2H, t, J=6.8 Hz), 7.43 (2H, d, J=6.8 Hz).

Production Example 616-3N-(4-Fluorophenyl)-N′-(4-hydroxy-2-methylphenyl)-N′-methylurea

After dissolving N-methyl-4-benzyloxy-2-methylaniline (2.64 g, 11.61mmol) in N,N-dimethylformamide (20 ml), sodium hydride (1.16 g, 29.00mmol, 60% in oil) was added and the mixture was stirred at 85° C. for 45minutes under a nitrogen atmosphere. Phenyl N-(4-fluorophenyl)carbamate(3.50 g, 12.76 mmol) was added and the mixture was further stirred at85° C. for 1 hour under a nitrogen atmosphere. After cooling to roomtemperature, water was added to the reaction solution, extraction wasperformed with ethyl acetate, the extract was washed with saturatedbrine and dried over anhydrous magnesium sulfate, and the solvent wasdistilled off under reduced pressure. The residue was adsorbed onto NHsilica gel and subjected to crude purification by NH silica gel columnchromatography acetate-ethanol) to obtainN′-(4-benzyloxy-2-methylphenyl)-N-(4-fluorophenyl)-N′-methylurea (2.66g) as a yellow oil. This was dissolved in methanol (50 ml), and then 10%palladium carbon (0.2 g) was added and the mixture was stirred for 2hours at room temperature under a hydrogen atmosphere. The catalyst wasfiltered off, and then filtrate was washed with ethanol, and the solventwas distilled off under reduced pressure. The precipitated crystals weresuspended in ethanol, the suspension was diluted with diethyl ether andhexane, and the crystals were filtered out, washed with hexane and driedby aspiration to obtain the title compound (0.83 g, 3.0258 mmol, 41.86%)as brown crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.07 (3H, s), 3.04 (3H, s), 6.63 (1H,d, J=8.0 Hz), 6.67 (1H, s), 6.97-7.03 (3H, m), 7.34-7.39 (2H, m), 7.54(1H, brs), 9.46 (1H, s).

Example 617N-{[4-(7-Benzyloxy-6-cyano-4-quinolyl)oxy]-2-methylphenyl]}-N′-(4-fluorophenyl)-N-methylurea

6-Cyano-4-chloro-7-methoxyquinoline (90 mg, 0.3038 mmol) andN-(4-fluorophenyl)-N′-(4-hydroxy-2-methylphenyl)-N′-methylurea (100 mg,0.3646 mmol) were dissolved in dimethylsulfoxide (3 ml), and then sodiumhydride (15 mg, 0.3646 mmol) was added and the mixture was heated andstirred at 85° C. for 1 hour. After cooling to room temperature, waterwas added to the reaction solution, extraction was performed with ethylacetate, the extract was washed with saturated brine and dried overanhydrous magnesium sulfate, and the solvent was distilled off underreduced pressure. The residue was purified by NH silica gel columnchromatography (ethyl acetate), and the obtained crystals were suspendedin diethyl ether and filtered out, washed with diethyl ether and driedby aspiration to obtain the title compound (80 mg, 0.1502 mmol, 49.44%)as pink crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.21 (3H, s), 3.16 (3H, s), 5.46 (2H,s), 6.76 (1H, d, J=5.4 Hz), 7.05 (2H, t, J=8.8 Hz), 7.20 (1H, dd, J=2.4Hz, 8.4 Hz), 7.29 (1H, d, J=2.4 Hz), 7.34-7.46 (6H, m), 7.54 (2H, d,J=6.8 Hz), 7.72 (1H, s), 7.91 (1H, brs), 8.75 (1H, s), 8.77 (1H, d,J=5.4 Hz).

Example 618N-{[4-(6-Carbamoyl-7-methoxy-4-quinolyl)oxy]-2-fluorophenyl]}-N′-(4-fluorophenyl)-N-methylurea

6-Carbamoyl-4-chloro-7-methoxyquinoline (41 mg, 0.1744 mmol) andN-(2-fluoro-4-hydroxyphenyl)-N′-(4-fluorophenyl)-N-methylurea (57 mg,0.2048 mmol) were dissolved in dimethylsulfoxide (1.0 ml), and thensodium hydride (8.4 mg, 0.2093 mmol) was added and the mixture washeated and stirred at 85° C. for 30 minutes. After cooling the reactionsolution to room temperature, water was added and the precipitatedcrystals were filtered out. The crystals were then suspended inacetone:diethyl ether=1:2 and refiltered out, washed with diethyl etherand dried by aspiration to obtain the title compound (46 mg, 0.0961mmol, 55.13%) as yellow crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.44 (3H, s), 4.01 (3H, s), 6.44 (1H,d, J=5.4 Hz), 6.99 (1H, brs), 7.10 (1H, dd, J=2.4 Hz, 8.4 Hz), 7.34 (2H,t, J=8.8 Hz), 7.38 (1H, d, J=8.4 Hz), 7.47 (1H, s), 7.59 (2H, dd, J=5.0Hz, 8.8 Hz), 7.69 (1H, brs), 7.81 (1H, brs), 8.59 (1H, d, J=5.4 Hz),8.69 (1H, s).

The starting materials were synthesized in the following manner.

Production Example 618-1 4-Benzyloxy-2-fluoronitrobenzene

3-Fluoro-4-nitrophenol (10 g, 63.65 mmol) was dissolved inN,N-dimethylformamide (120 ml), and then sodium hydride (2.68 g, 67.00mmol, 60% in oil) was added and the mixture was stirred for 15 minutesat room temperature under a nitrogen atmosphere. After adding benzylbromide (7.6 ml, 63.65 mmol), the mixture was stirred overnight at roomtemperature under a nitrogen atmosphere. Water was added to the reactionsolution, and the precipitated crystals were filtered out, washed withwater and dried by aspiration to obtain the title compound (16.06 g,quant.) as crude light yellow crystals. These were used without furtherpurification for the following reaction.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 5.25 (2H, s), 7.04 (1H, dd, J=1.6 Hz,9.2 Hz), 7.27 (1H, dd, J=2.8 Hz, 14.0 Hz), 7.32-7.42 (3H, m), 7.46 (2H,d, J=6.8 Hz), 8.15 (1H, t, J=9.2 Hz).

Production Example 618-2 4-Benzyloxy-2-fluoroaniline

After dissolving the 4-benzyloxy-2-fluoronitrobenzene crude crystals(16.06 g, 63.65 mmol) in ethanol (1000 ml) and water (200 ml),electrolytic iron powder (14.0 g, 254.60 mmol) and ammonium chloride(27.2 g, 509.20 mmol) were added and the mixture was heated to refluxfor 4.5 hours. The reaction solution was cooled to near roomtemperature, the insoluble portion was filtered off, washing wasperformed with ethanol and the solvent of the filtrate was distilled offunder reduced pressure. The residue was dissolved in ethyl acetate,washed with saturated brine and dried over anhydrous magnesium sulfate,and the solvent was distilled off under reduced pressure. The residuewas adsorbed onto silica gel and purified by silica gel columnchromatography (hexane-ethyl acetate system) to obtain the titlecompound (11.25 g, 51.78 mmol, 81.35%) as a brown oil.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 3.44 (2H, brs), 4.98 (2H, s), 6.10 (1H,dd, J=2.8 Hz, 8.8 Hz), 6.68-6.74 (2H, m), 7.30-7.43 (5H, m).

Production Example 618-3N-{1-(1H-Benzotriazolyl)methyl}-4-benzyloxy-2-fluoroaniline

After dissolving 4-benzyloxy-2-fluoroaniline (11.25 g, 51.78 mmol) inmethanol (300 ml), 1H-benzotriazole-1-methanol (8.11 g, 54.37 mmol) wasadded and the mixture was stirred for 10 hours at room temperature. Theprecipitated crystals were filtered out, washed with ethanol and driedby aspiration to obtain the title compound (12.01 g, 34.47 mmol, 66.57%)as colorless crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 4.92 (2H, s), 6.07 (2H, d, J=6.8 Hz),6.64 (1H, dd, J=2.8 Hz, 9.2 Hz), 6.78 (1H, dd, J=2.8 Hz, 9.2 Hz), 6.82(1H, m), 6.99 (1H, t, J=9.2 Hz), 7.24-7.38 (6H, m), 7.53 (1H, t, J=8.4Hz), 7.99 (1H, d, J=8.4 Hz), 8.10 (1H, d, J=8.4 Hz).

Production Example 618-4 N-Methyl-4-benzyloxy-2-fluoroaniline

After dissolvingN-{1-(1H-benzotriazolyl)methyl}-4-benzyloxy-2-fluoroaniline (14.13 g,40.56 mmol) in N,N-dimethylformamide (200 ml), methanol (150 ml) andethanol (50 ml), there was added sodium borohydride (3.06 g, 81.12 mmol)and the mixture was stirred for 2.5 hours at room temperature. There wasfurther added sodium borohydride (0.78 g, 20.28 mmol), and the mixturewas stirred for 13.5 hours at room temperature. Water was added to thereaction solution, extraction was performed with ethylacetate-tetrahydrofuran, the extract was washed with saturated brine anddried over anhydrous magnesium sulfate, and the solvent was distilledoff under reduced pressure. The residue was adsorbed onto silica gel andpurified by silica gel column chromatography (hexane-ethyl acetatesystem) to obtain the title compound (5.98 g, 26.31 mmol, 64.87%) aslight yellow crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.64 (3H, d, J=4.8 Hz), 4.97 (2H, s),5.02 (1H, d, J=4.8 Hz), 6.55 (1H, t, J=9.2 Hz), 6.68 (1H, d, J=9.2 Hz),6.79 (1H, J=13.2 Hz), 7.25-7.50 (5H, m).

Production Example 618-5N-(4-Benzyloxy-2-fluorophenyl)-N′-(4-fluorophenyl)-N-methylurea

N-Methyl-4-benzyloxy-2-fluoroaniline (250 mg, 1.0805 mmol) was dissolvedin N,N-dimethylformamide (5.0 ml), and then sodium hydride (65 mg,1.6207 mmol, 60% in oil) was added and the mixture was stirred at 95° C.for 45 minutes under a nitrogen atmosphere. After adding 4-fluorophenylisocyanate (0.14 ml, 1.1836 mmol), the mixture was stirred at 85° C. for45 minutes under a nitrogen atmosphere. There was further added4-fluorophenyl isocyanate (0.14 ml, 0.5094 mmol), and the mixture wasstirred at 85° C. for 30 minutes under a nitrogen atmosphere. Aftercooling to room temperature, water was added to the reaction solution,extraction was performed with ethyl acetate, the extract was washed withsaturated brine and dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure. The residue wasadsorbed onto NH silica gel and purified by NH silica gel columnchromatography (hexane-ethyl acetate system) to obtain the titlecompound (0.105 g, 0.2881 mmol, 21.67%) as a light yellow oil.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 2.16 (3H, s), 3.44 (3H, s), 5.01 (2H,s), 6.90 (1H, d, J=2.0 Hz), 6.78 (1H, dd, J=2.0 Hz, 8.4 Hz), 6.91 (1H,d, J=8.4 Hz), 7.19 (2H, t, J=8.4 Hz), 7.30-7.46 (5H, m).

Production Example 618-6N-(2-Fluoro-4-hydroxyphenyl)-N′-(4-fluorophenyl)-N-methylurea

After dissolvingN-(4-benzyloxy-2-fluorophenyl)-N′-(4-fluorophenyl)-N-methylurea (105 mg,0.2881 mmol) in methanol (10 ml), 10% palladium carbon (20 mg) was addedand the mixture was stirred for 45 minutes at room temperature under ahydrogen atmosphere. The catalyst was filtered off, and then was washedwith ethanol, and the solvent of the filtrate was distilled off underreduced pressure. The precipitated crystals were suspended in diethylether, and then filtered out, washed with diethyl ether and dried byaspiration to obtain the title compound (57 mg, 0.2048 mmol, 71.10%) ascolorless crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.07 (3H, s), 6.41 (1H, d, J=1.6 Hz),6.54 (1H, dd, J=1.6 Hz, 8.4 Hz), 7.00 (1H, d, J=8.4 Hz), 7.38 (2H, t,J=8.8 Hz), 7.53 (2H, dd, J=4.8 Hz, 8.8 Hz).

Example 619N-Cyclopropyl-N′-{[4-(6-(methoxy)carbamoyl-7-methoxy-4-quinolyl)oxy]-2-fluorophenyl})urea

N-{[4-(6-carboxyl-7-methoxy-4-quinolyl)oxy]-2-fluorophenyl}}-N′-cyclopropylurea(40 mg, 0.0972 mmol) and O-methylhydroxylamine hydrochloride (16 mg,0.1945 mmol) were used for reaction in the same manner as Example 412.After completion of the reaction, water was added to the reactionsolution, extraction was performed with ethyl acetate, the extract waswashed with saturated brine and dried over anhydrous magnesium sulfate,and the solvent was distilled off under reduced pressure. The obtainedcrystals were suspended in acetone and diluted with diethyl ether, andthe crystals were filtered out, washed with diethyl ether and dried byaspiration to obtain the title compound (20 mg, 0.0454 mmol, 46.71%) aslight yellow crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.41 (2H, m), 0.66 (2H, m), 2.56 (1H,m), 3.75 (3H, s), 3.99 (3H, s), 6.54 (1H, d, J=5.0 Hz), 6.82 (1H, s),7.08 (1H, d, J=8.4 Hz), 7.32 (1H, d, J=8.4 Hz), 7.50 (1H, s), 8.19-8.24(2H, m), 8.43 (1H, s), 8.67 (1H, d, J=5.0 Hz), 11.46 (1H, s).

Example 620N-Cyclopropyl-N′-{[4-(6-(2-ethoxyethyl)carbamoyl-7-methoxy-4-quinolyl)oxy]-2-fluorophenyl]}urea

N-{[4-(6-carboxyl-7-methoxy-4-quinolyl)oxy]-2-fluorophenyl]}-N′-cyclopropylurea(40 mg, 0.0972 mmol) and 2-ethoxyethylamine (17 mg, 0.1945 mmol) wereused for reaction in the same manner as Example 412. After completion ofthe reaction, water was added to the reaction solution, and theprecipitated crystals were filtered out. These were suspended in acetoneand diluted with diethyl ether, and then the crystals were filtered out,washed with diethyl ether and dried by aspiration to obtain the titlecompound (33 mg, 0.0684 mmol, 70.93%) as light yellow crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.39-0.44 (2H, m), 0.63-0.68 (2H, m),1.14 (3H, t, J=6.6 Hz), 2.57 (1H, m), 3.46-3.55 (6H, m), 4.04 (3H, s),6.54 (1H, d, J=5.2 Hz), 6.81 (1H, m), 7.08 (1H, m), 7.33 (1H, dd, J=2.4Hz, 11.6 Hz), 7.53 (1H, s), 8.19-8.24 (2H, m), 8.46 (1H, t, J=5.2 Hz),8.63 (1H, s), 8.68 (1H, d, J=5.2 Hz).

Example 621N-Cyclopropyl-N′-{[4-(6-(2-fluorocyclopropyl)carbamoyl-7-methoxy-4-quinolyl)oxy]-2-fluorophenyl]}urea

N-{[4-(6-carboxyl-7-methoxy-4-quinolyl)oxy]-2-fluorophenyl]}-N′-cyclopropylurea(40 mg, 0.0972 mmol) and 2-fluorocyclopropylamine tosylate (39 mg,0.1945 mmol) were used for reaction in the same manner as Example 412.After completion of the reaction, water was added to the reactionsolution, extraction was performed with ethyl acetate, the extract waswashed with saturated brine and dried over anhydrous magnesium sulfate,and the solvent was distilled off under reduced pressure. The residuewas adsorbed onto silica gel and purified by silica gel columnchromatography (ethyl acetate-ethanol system), and the obtained crystalswere suspended in acetone:diethyl ether=1:3 and filtered out, washedwith diethyl ether and dried by aspiration to obtain the title compound(12 mg, 0.0256 mmol, 26.35%) as colorless crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.42 (2H, m), 0.65 (2H, m), 1.05-1.18(2H, m), 2.56 (1H, m), 2.93 (1H, m), 4.01 (3H, m), 4.54-4.93 (1H, m),6.54 (1H, d, J=5.2 Hz), 6.80 (1H, m), 7.08 (1H, m), 7.32 (1H, dd, J=2.0Hz, 11.6 Hz), 7.53 (1H, s), 8.22 (2H, m), 8.45 (1H, m), 8.52 (1H, s),8.67 (1H, d, J=5.2 Hz).

Example 622N-{[4-(6-(2-Cyanoethyl)carbamoyl-7-methoxy-4-quinolyl)oxy]-2-fluorophenyl]}-N′-cyclopropylurea

N-{[4-(6-carboxyl-7-methoxy-4-quinolyl)oxy]-2-fluorophenyl]}-N′-cyclopropylurea(40 mg, 0.0972 mmol) and 2-cyanoethylamine (14 mg, 0.1945 mmol) wereused for reaction in the same manner as Example 412. After completion ofthe reaction, water was added to the reaction solution, extraction wasperformed with ethyl acetate, the extract was washed with saturatedbrine and dried over anhydrous magnesium sulfate, and the solvent wasdistilled off under reduced pressure. The obtained crystals weresuspended in acetone and diluted with diethyl ether, and then thecrystals were filtered out, washed with diethyl ether and dried byaspiration to obtain the title compound (18 mg, 0.0684 mmol, 39.96%) aslight yellow crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.41 (2H, m), 0.63-0.66 (2H, m), 2.56(1H, m), 2.82 (2H, t, J=6.4 Hz), 3.57 (2H, q, J=6.4 Hz), 4.03 (3H, s),6.54 (1H, d, J=5.2 Hz), 6.81 (1H, m), 7.08 (1H, m), 7.32 (1H, dd, J=2.4Hz, 11.6 Hz), 7.54 (1H, s), 8.18-8.26 (2H, m), 8.61 (1H, s), 8.68 (1H,d, J=5.2 Hz), 8.73 (1H, m).

Example 623N-[4-(6-Carbamoyl-7-methoxy-4-quinolyl)oxy-2-methylphenyl]-N′-methylurea

[4-(6-Carbamoyl-7-methoxy-4-quinolyl)oxy-2-methylphenyl]carbamic acidphenyl ester (70 mg) was added to dimethylsulfoxide (0.8 ml), and then amethylamine-containing 2N tetrahydrofuran solution (0.4 ml) was addedand the mixture was stirred for 5 minutes. Water and ethyl acetate wereadded to the reaction solution, and the precipitated crystals werefiltered out to obtain the title compound (48 mg).

¹H-NMR (DMSO-d₆) δ (ppm) 2.20 (3H, s), 2.65 (3H, d, J=4.8 Hz), 4.01 (3H,s), 6.38-6.47 (2H, m), 7.00-7.05 (1H, m), 7.09 (1H, d, J=2.8 Hz), 7.49(1H, s), 7.71 (1H, brs), 7.74 (1H, s), 7.84 (1H, brs), 7.86-7.92 (1H,m), 8.63 (1H, d, J=5.2 Hz), 8.66 (1H, s)

Example 624N-[4-(6-Carbamoyl-7-methoxy-4-quinolyl)oxy-2-methyl-phenyl]-N′-ethylurea

[4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2-methyl-phenyl]-carbamic acidphenyl ester (65 mg) was added to dimethylsulfoxide (1.0 ml), and thenan ethylamine-containing 2N tetrahydrofuran solution (0.37 ml) was addedand the mixture was stirred for 5 minutes. Water and ethyl acetate wereadded to the reaction solution, and the precipitated crystals werefiltered out to obtain the title compound (38 mg).

¹H-NMR (DMSO-d₆) δ (ppm) 1.06 (3H, t, J=7.2 Hz), 2.20 (3H, s), 3.06-3.16(2H, m), 4.01 (3H, s), 6.44 (1H, d, J=5.6 Hz), 6.49-6.45 (1H, m),7.00-7.04 (1H, m), 7.09 (1H, d, J=2.8 Hz), 7.49 (1H, s), 7.68 (1H, s),7.71 (1H, brs), 7.84 (1H, brs), 7.88-7.95 (1H, m), 8.63 (1H, d, J=5.6Hz), 8.66 (1H, s)

Example 625N-[2-Fluoro-4-([6-cyano-7-([3-(1-piperidino)propyl]oxy)-4-quinolyl]oxy)phenyl]-N′-cyclopropylurea

Cyclopropylamine (0.05 ml) was added to dimethylsulfoxide (0.5 ml), andthen[2-fluoro-4-([6-cyano-7-([3-(1-piperidino)propyl]oxy)-4-quinolyl]oxy)phenyl]carbamicacid phenyl ester (66 mg) was dissolved therein and the solution wasstirred for 10 minutes. Water and ethyl acetate were added to thereaction solution, and the precipitated crystals were filtered out toobtain the title compound (33 mg).

¹H-NMR (DMSO-d₆) δ (ppm) 0.38-0.45 (2H, m), 0.61-0.69 (2H, m), 1.30-1.55(6H, m), 1.92-2.02 (2H, m), 2.30-2.50 (6H, m), 2.53-2.59 (1H, m), 4.33(2H, t, J=6.0 Hz), 6.59 (1H, d, J=5.6 Hz), 6.82-6.86 (1H, m), 7.07-7.13(1H, m), 7.31-7.37 (1H, m), 7.61 (1H, s), 8.20-8.29 (2H, m), 8.72-8.77(2H, m)

The starting material was synthesized in the following manner.

Production Example 625-1[2-Fluoro-4-([6-cyano-7-([3-(1-piperidino)propyl]oxy)-4-quinolyl]oxy)phenyl]carbamicacid phenyl ester

The title compound (33 mg) was obtained from2-fluoro-4-([6-cyano-7-([3-(1-piperidino)propyl]oxy)-4-quinolyl]oxy)phenylamine(66 mg), by the method described in Production Example 141-1.

¹H-NMR (DMSO-d₆) δ (ppm) 1.40-1.75 (6H, m), 1.90-2.15 (4H, m) 2.50-2.67(2H, m), 3.13-3.27 (2H, m), 4.30-4.38 (2H, m), 6.54 (1H, d, J=5.2 Hz),6.97-7.06 (2H, m), 7.20-7.30 (6H, m), 8.01 (1H, s), 8.27 (1H, brs), 8.66(1H, s), 8.72 (1H, d, J=5.2 Hz)

Example 626N-[4-(7-Benzyloxy-6-cyanoquinolin-4-yloxy)-2-chloro-phenyl]-N′-methylurea

[4-(7-Benzyloxy-6-cyanoquinolin-4-yloxy)-2-chlorophenyl]carbamic acidphenyl ester (1.17 g) was added to dimethylformamide (6 ml), and then amethylamine-containing 2N tetrahydrofuran solution (0.4 ml) was addedand the mixture was stirred for 10 minutes. Water (15 ml) was added, andthe precipitated crystals were filtered out and washed with diethylether to obtain the title compound (968 mg).

¹H-NMR (DMSO-d₆) δ (ppm) 2.66 (3H, d, J=4.0 Hz), 5.45 (2H, s), 6.59 (1H,d, J=5.2 Hz), 6.86-6.92 (1H, m), 7.24 (1H, dd, J=8.8, 4.8 Hz), 7.32-7.57(6H, m), 7.71 (1H, s), 8.12 (1H, s), 8.21-8.28 (1H, m), 8.73 (1H, d,J=5.2 Hz), 8.76 (1H, s)

The starting material was synthesized in the following manner.

Production Example 626-1[4-(7-Benzyloxy-6-cyanoquinolin-4-yloxy)-2-chlorophenyl]-carbamic acidphenyl ester

The title compound (1.69 mg) was obtained from4-(4-amino-3-chlorophenyl)-7-benzyloxy-6-cyanoquinoline (1.68 g), by themethod described in Production Example 141-1.

¹H-NMR (DMSO-d₆) δ (ppm) 5.28 (2H, s), 6.44 (1H, d, J=5.2 Hz), 7.09 (1H,dd, J=2.8, 9.2 Hz), 7.13-7.50 (13H, m), 8.24-8.30 (1H, m), 8.60-8.65(2H, m)

Example 627N-[2-Chloro-4-(6-cyano-7-hydroxyquinolin-4-yloxy)-phenyl]-N′-methylurea

After addingN-[4-(7-benzyloxy-6-cyanoquinolin-4-yloxy)-2-chlorophenyl]-N′-methylurea(968 mg) and thioanisole (3.7 ml) to trifluoroacetic acid (10 ml), themixture was stirred overnight at 50° C. It was then concentrated underreduced pressure, ethyl acetate and aqueous sodium bicarbonate wereadded and the precipitated crystals were filtered out and washed withethyl acetate to obtain the title compound (849 mg).

¹H-NMR (DMSO-d₆) δ (ppm) 2.66 (3H, d, J=4.0 Hz), 5.30 (1H, d, J=5.2 Hz),6.37 (1H, s), 6.83-6.90 (1H, m), 7.12-7.16 (1H, m), 7.33-7.35 (1H, m),8.00 (1H, s), 8.08 (1H, brs), 8.14-8.19 (2H, m)

Example 628N-(4-{6-Cyano-7-[(2R)-oxiran-2-yl]methoxyquinolin-4-yloxy}-2-chlorophenyl)-N′-methylurea

N-[2-Chloro-4-(6-cyano-7-hydroxyquinolin-4-yloxy)phenyl]-N′-methylurea(600 mg) was added to dimethylformamide (4 ml), and then(2R)-(−)-glycidyl p-toluenesulfonate (484 mg) and potassium carbonate(450 mg) were added thereto and the mixture was heated at 50° C. for 4hours. Water was added to the reaction solution, extraction wasperformed with ethyl acetate, the organic layer was washed with waterand saturated brine in that order and dried over anhydrous sodiumsulfate, and the solvent was distilled off under reduced pressure. Theobtained crude product was recrystallized with ethyl acetate to obtainthe title compound (650 mg) as light yellow crystals.

¹H-NMR (DMSO-d₆) δ (ppm) 2.68 (3H, d, J=4.8 Hz), 2.80-2.96 (2H, m),3.45-3.51 (1H, m), 4.18 (1H, dd, J=11.6, 6.4 Hz), 4.73 (1H, dd, J=11.6,2.0 Hz), 6.61 (1H, d, J=5.2 Hz), 6.86-6.93 (1H, m), 7.26 (1H, dd, J=9.2,2.8 Hz), 7.51 (1H, d, J=2.8 Hz), 7.66 (1H, s), 8.14 (1H, s), 8.27 (1H,d, J=9.2 Hz), 8.75 (1H, d, J=5.2 Hz), 8.78 (1H. s)

Example 629N-(4-{6-Cyano-7-[(2R)-2-hydroxy-3-pyrrolidin-1-ylpropoxy]quinolin-4-yloxy}-2-chlorophenyl)-N′-methylurea

After adding tetrahydrofuran (1.0 ml) and pyrrolidine (0.10 ml) toN-(4-{6-cyano-7-[(2R)-oxiran-2-yl]methoxyquinolin-4-yloxy}-2-chlorophenyl)-N′-methylurea(110 mg), the mixture was heated at 60° C. for 2 hours. The reactionsolution was purified by NH silica gel column chromatography (ethylacetate-methanol system) to obtain the title compound (65 mg) as lightyellow crystals.

¹H-NMR (DMSO-d₆) δ (ppm) 1.55-1.73 (4H, m), 2.45-2.58 (5H, m) 2.68-2.77(4H, m), 4.00-4.06 (1H, m), 4.22 (1H, dd, J=10.4, 5.6 Hz), 4.32 (1H, dd,J=10.4, 3.2 Hz), 5.00-5.05 (1H, m), 6.59 (1H, d, J=5.2 Hz), 6.86-6.93(1H, m), 7.26 (1H, dd, J=9.2, 2.8 Hz), 7.51 (1H, d, J=2.8 Hz), 7.63 (1H,s), 8.14 (1H, brs), 8.27 (1H, dd, J=9.2, 2.8 Hz), 8.72-8.76 (2H, m).

Example 630N-(4-{6-Cyano-7-[(2R)-2-hydroxy-3-piperidin-1-ylpropoxy]quinolin-4-yloxy}-2-chlorophenyl)-N′-methylurea

After adding tetrahydrofuran (2.0 ml) and piperidine (0.20 ml) toN-(4-{6-cyano-7-[(2R)-oxiran-2-yl]methoxyquinolin-4-yloxy}-2-chlorophenyl)-N′-methylurea(110 mg), the mixture was heated at 60° C. for 3 hours. The reactionsolution was purified by NH silica gel column chromatography (ethylacetate-methanol system) to obtain the title compound (80 mg) as lightyellow crystals.

¹H-NMR (DMSO-d₆) δ (ppm) 1.30-1.42 (2H, m), 1.45-1.57 (4H, m), 2.35-2.50(6H, m), 2.68 (3H, d, J=4.4 Hz), 4.00-4.08 (1H, m), 4.22 (1H, dd,J=10.4, 6.0 Hz), 4.32 (1H, dd, J=10.4, 3.2 Hz), 4.93-4.97 (1H, m), 6.59(1H, d, J=5.6 Hz), 6.86-6.93 (1H, m), 7.26 (1H, dd, J=9.2, 2.8 Hz), 7.51(1H, d, J=2.8 Hz), 7.64 (1H, s), 8.14 (1H, brs), 8.27 (1H, dd, J=9.2,2.8 Hz), 8.72-8.76 (2H, m).

Example 631N-(4-{6-Cyano-7-[3-diethylamino-(2R)-2-hydroxypropoxy]quinolin-4-yloxy}-2-chlorophenyl)-N′-methylurea

After adding tetrahydrofuran (3.0 ml) and diethylamine (1.50 ml) toN-(4-{6-cyano-7-[(2R)-oxiran-2-yl]methoxyquinolin-4-yloxy}-2-chlorophenyl)-N′-methylurea(100 mg), the mixture was heated at 60° C. for 5 hours. The reactionsolution was purified by NH silica gel column chromatography (ethylacetate-methanol) to obtain the title compound (75 mg) as light yellowcrystals.

¹H-NMR (DMSO-d₆) δ (ppm) 0.98 (6H, t, J=7.2 Hz), 2.40-2.70 (9H, m),3.93-4.00 (1H, m), 4.23 (1H, dd, J=10.4, 5.6 Hz), 4.32 (1H, dd, J=10.4,3.6 Hz), 4.93 (1H, brs), 6.59 (1H, d, J=5.6 Hz), 6.86-6.93 (1H, m), 7.26(1H, dd, J=9.2, 2.8 Hz), 7.51 (1H, d, J=2.8 Hz), 7.63 (1H, s), 8.14 (1H,brs), 8.27 (1H, dd, J=9.2, 2.8 Hz), 8.72-8.76 (2H, m).

Example 632 Methyl4-(3-chloro-4-(((methylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylate

PhenylN-(2-chloro-4-(7-methoxy-6-methoxycarbonyl-4-quinolyl)oxyphenyl)carbamate(1.92 g, 4.00 mmol) and 40% methylamine (methanol solution) (2 ml) werestirred in dimethylformamide (8 ml) at room temperature for 30 minutes.The reaction solution was distributed between ethyl acetate and water,the organic layer was washed with water and saturated brine and driedover anhydrous magnesium sulfate, and the drying agent was filtered outand the filtrate distilled off under reduced pressure. The obtainedcrude product was suspended in ethyl acetate, the suspension was dilutedwith hexane, and the crystals were filtered out, washed with hexane andblow-dried to obtain the title compound (1.41 g, 3.39 mmol, 85%) aswhite crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.68 (3H, d, J=4.4 Hz), 3.87 (3H, s),3.99 (3H, s), 6.54 (1H, d, J=5.2 Hz), 6.89 (1H, q, J=4.4 Hz), 7.25 (1H,dd, J=2.8, 9.0 Hz), 7.50 (1H, d, J=2.8 Hz), 7.54 (1H, s), 8.13 (1H, s),8.26 (1H, d, J=9.0 Hz), 8.58 (1H, s), 8.69 (1H, d, J=5.2 Hz).

Example 6334-(3-Chloro-4-(((methylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid

After adding methanol (14 ml) and a 2N sodium hydroxide aqueous solution(7 ml) to methyl4-(3-chloro-4-(((methylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylate(1.31 g, 3.15 mmol), the mixture was stirred at 60° C. for 30 minutes.The reaction solution was cooled to room temperature, 2N hydrochloricacid was added for neutralization, the methanol was distilled off, andthe precipitated white crystals were filtered out, thoroughly washedwith water and dried at 60° C. to obtain the title compound (1.26 g,3.15 mmol, 100%).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.68 (3H, d, J=4.4 Hz), 3.98 (3H, s),6.54 (1H, d, J=5.0 Hz), 6.89 (1H, q, J=4.4 Hz), 7.25 (1H, dd, J=2.8, 9.0Hz), 7.48-7.53 (2H, m), 8.13 (1H, s), 8.25 (1H, d, J=9.0 Hz), 8.54 (1H,s), 8.69 (1H, d, J=5.0 Hz), 13.12 (1H, brs).

Example 634N6-Methyl-4-(3-chloro-4-(((methylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

After dissolving4-(3-chloro-4-(((methylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid (100 mg, 0.250 mmol) in dimethylformamide (3 ml), there were addeda 40% methylamine-methanol solution (0.100 ml), triethylamine (0.250 ml)and1H-1,2,3-benzotriazol-1-yloxy)(tri(dimethylamino))phosphoniumhexafluorophosphate(221 mg, 0.500 mmol) in that order at room temperature, and the mixturewas stirred for 15 hours. The reaction solution was distributed betweenethyl acetate and water, and the organic layer was washed with water andsaturated brine and dried over anhydrous magnesium sulfate. The solventwas distilled off, the residue was suspended in ethyl acetate anddiluted with hexane, and the crystals were filtered out and blow-driedto obtain the title compound (85.0 mg, 0.204 mmol, 82%) as whitecrystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.68 (3H, d, J=4.2 Hz), 2.84 (3H, d,J=4.2 Hz), 4.02 (3H, s), 6.53 (1H, d, J=5.2 Hz), 6.88 (1H, q, J=4.2 Hz),7.22 (1H, dd, J=2.8, 9.2 Hz), 7.45 (1H, d, J=2.8 Hz), 7.52 (1H, s), 8.12(1H, s), 8.24 (1H, d, J=9.2 Hz), 8.36 (1H, q, J=4.2 Hz), 8.59 (1H, s),8.67 (1H, d, J=5.2 Hz).

Example 635N6-Ethyl-4-(3-chloro-4-(((methylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (93.0 mg, 0.217 mmol, 87%) was obtained as whitecrystals from4-(3-chloro-4-(((methylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid (100 mg, 0.250 mmol) and 2.0M ethylamine (tetrahydrofuransolution), by the same procedure as in Example 634.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.15 (3H, t, J=7.2 Hz), 2.68 (3H, d,J=4.4 Hz), 3.28-3.38 (2H, m), 4.02 (3H, s), 6.53 (1H, d, J=5.2 Hz), 6.87(1H, q, J=4.4 Hz), 7.21 (1H, dd, J=2.8, 9.2 Hz), 7.47 (1H, d, J=2.8 Hz),7.51 (1H, s), 8.11 (1H, s), 8.25 (1H, d, J=9.2 Hz), 8.38 (1H, m), 8.54(1H, s), 8.66 (1H, d, J=5.2 Hz).

Example 636N6-Cyclopropyl-4-(3-chloro-4-(((methylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (66.0 mg, 0.150 mmol, 60%) was obtained as whitecrystals from4-(3-chloro-4-(((methylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid (100 mg, 0.250 mmol) and cyclopropylamine, by the same procedure asin Example 634.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.59 (2H, m), 0.69 (2H, m), 2.68 (3H,d, J=4.8 Hz), 2.87 (1H, m), 3.99 (3H, s), 6.53 (1H, d, J=5.2 Hz), 6.88(1H, q, J=4.8 Hz), 7.22 (1H, dd, J=2.8, 9.2 Hz), 7.47 (1H, d, J=2.8 Hz),7.49 (1H, s), 8.12 (1H, s), 8.25 (1H, d, J=9.2 Hz), 8.34 (1H, d, J=4.0Hz), 8.41 (1H, s), 8.66 (1H, d, J=5.2 Hz).

Example 637N6-Methoxy-4-(3-chloro-4-(((methylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (51.0 mg, 0.118 mmol, 47%) was obtained as whitecrystals from4-(3-chloro-4-(((methylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid (100 mg, 0.250 mmol) and methoxylamine hydrochloride, by the sameprocedure as in Example 634.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.56 (3H, d, J=4.4 Hz), 3.74 (3H, s),3.99 (3H, s), 6.54 (1H, d, J=5.2 Hz), 6.88 (1H, q, J=4.4 Hz), 7.24 (1H,dd, J=2.8, 9.2 Hz), 7.48 (1H, d, J=2.8 Hz), 7.50 (1H, s), 8.12 (1H, s),8.25 (1H, d, J=9.2 Hz), 8.43 (1H, s), 8.67 (1H, d, J=5.2 Hz), 11.46 (1H,s).

Example 638N6-(2-Methoxyethyl)-4-(3-chloro-4-(((methylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (71.0 mg, 0.154 mmol, 62%) was obtained as whitecrystals from4-(3-chloro-4-(((methylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid (100 mg, 0.250 mmol) and 2-methoxyethylamine, by the same procedureas in Example 634.

¹H-NMR Spectrum (DMSO-d₆) d (ppm): 2.68 (3H, d, J=4.4 Hz), 3.30 (3H, s),3.46-3.52 (4H, m), 4.03 (3H, s), 6.54 (1H, d, J=5.2 Hz), 6.88 (1H, q,J=4.4 Hz), 7.23 (1H, dd, J=2.8, 9.2 Hz), 7.48 (1H, d, J=2.8 Hz), 7.53(1H, s), 8.12 (1H, s), 8.25 (1H, d, J=9.2 Hz), 8.46 (1H, m), 8.61 (1H,s), 8.67 (1H, d, J=5.2 Hz).

Example 639N6-(2-Fluoroethyl)-4-(3-chloro-4-(((methylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (86.0 mg, 0.192 mmol, 77%) was obtained as whitecrystals from4-(3-chloro-4-(((methylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid (100 mg, 0.250 mmol) and 2-fluoroethylamine hydrochloride, by thesame procedure as in Example 634.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.68 (3H, d, J=4.4 Hz), 3.59 (1H, m),3.67 (1H, m), 4.03 (3H, s), 4.50 (1H, m), 4.62 (1H, m), 6.54 (1H, d,J=5.2 Hz), 6.88 (1H, q, J=4.4 Hz), 7.24 (1H, dd, J=2.8, 9.2 Hz), 7.48(1H, d, J=2.8 Hz), 7.53 (1H, s), 8.12 (1H, s), 8.24 (1H, d, J=9.2 Hz),8.58-8.62 (2H, m), 8.67 (1H, d, J=5.2 Hz).

Example 640N6-((2R)Tetrahydro-2-furanylmethyl)-4-(3-chloro-4-(((methylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (81.0 mg, 0.167 mmol, 67%) was obtained as a whitepowder from4-(3-chloro-4-(((methylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid (100 mg, 0.250 mmol) and R-tetrahydrofurfurylamine, by the sameprocedure as in Example 634.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.62 (1H, m), 1.80-2.00 (3H, m), 2.68(3H, d, J=4.4 Hz), 3.40 (2H, m), 3.66 (1H, dd, J=3.6, 14.0 Hz), 3.81(1H, dd, J=4.0, 14.0 Hz), 3.99 (1H, m), 4.02 (3H, s), 6.54 (1H, d, J=5.2Hz), 6.88 (1H, q, J=4.4 Hz), 7.23 (1H, dd, J=2.8, 8.8 Hz), 7.48 (1H, d,J=2.8 Hz), 7.54 (1H, s), 8.12 (1H, s), 8.24 (1H, d, J=8.8 Hz), 8.43 (1H,m), 8.61 (1H, s), 8.67 (1H, d, J=5.2 Hz).

Example 641N6-((2S)Tetrahydro-2-furanylmethyl)-4-(3-chloro-4-(((methylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (85.0 mg, 0.175 mmol, 70%) was obtained as a whitepowder from4-(3-chloro-4-(((methylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid (100 mg, 0.250 mmol) and S-tetrahydrofurfurylamine), by the sameprocedure as in Example 634.

Example 642N6-(2-Ethoxyethyl)-4-(3-chloro-4-(((methylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (94.0 mg, 0.199 mmol, 80%) was obtained as a whitepowder from4-(3-chloro-4-(((methylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid (100 mg, 0.250 mmol) and 2-ethoxyethylamine, by the same procedureas in Example 634.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.15 (3H, t, J=6.8 Hz), 2.68 (3H, d,J=4.4 Hz), 3.45-3.56 (6H, m), 4.04 (3H, s), 6.54 (1H, d, J=5.2 Hz), 6.89(1H, q, J=4.4 Hz), 7.23 (1H, dd, J=2.8, 9.2 Hz), 7.48 (1H, d, J=2.8 Hz),7.54 (1H, s), 8.13 (1H, s), 8.25 (1H, dd, J=2.8, 9.2 Hz), 8.46 (1H, m),8.64 (1H, s), 8.67 (1H, d, J=5.2 Hz).

Example 643N6-Isobutoxy-4-(3-chloro-4-(((methylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (72.0 mg, 0.152 mmol, 61%) was obtained as a whitepowder from4-(3-chloro-4-(((methylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid (100 mg, 0.250 mmol) and isobutoxylamine hydrochloride, by the sameprocedure as in Example 634.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.95 (6H, d, J=6.8 Hz), 1.97 (1H, m),2.68 (3H, d, J=4.4 Hz), 3.71 (2H, d, J=6.8 Hz), 3.99 (3H, s), 6.54 (1H,d, J=5.2 Hz), 6.89 (1H, q, J=4.4 Hz), 7.23 (1H, dd, J=2.8, 9.2 Hz), 7.48(1H, d, J=2.8 Hz), 7.50 (1H, s), 8.13 (1H, s), 8.25 (1H, dd, J=2.8, 9.2Hz), 8.36 (1H, s), 8.67 (1H, d, J=5.2 Hz), 11.35 (1H, br s).

Example 6444-(3-Chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-((2R)-3-diethylamino-2-hydroxypropoxy)-6-quinolinecarboxamide

After adding (2R)oxiran-2-ylmethyl 4-methyl-1-benzenesulfonate (308 mg,1.35 mmol), potassium carbonate (149 mg, 1.08 mmol) anddimethylformamide (9 ml) to4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-hydroxy-6-quinolinecarboxamide(372.0 mg, 0.90 mmol), the mixture was stirred at 60° C. for 6 hours.Next, diethylamine (2 ml) was added and the mixture was further stirredovernight at 50° C. The reaction solution was distributed between ethylacetate and water, and the organic layer was washed with water andsaturated brine and then dried over anhydrous sodium sulfate. Thesolvent was distilled off, the residue was subjected to silica gelcolumn chromatography (eluent—ethyl acetate:methanol=95:5), the fractioncontaining the target substance was concentrated, and crystals wereprecipitated from diethyl ether, filtered out and blow-dried to obtainthe title compound (177.5 mg, 0.327 mmol, 36.3%) as white crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.42 (2H, m), 0.65 (2H, m), 0.94 (6H,t, J=7.2 Hz), 2.44-2.60 (7H, m), 3.98 (1H, m), 4.21 (1H, dd, J=5.6, 10.0Hz), 4.31 (1H, dd, J=3.2, 10.0 Hz), 5.09 (1H, d, J=4.4 Hz), 6.51 (1H, d,J=5.2 Hz), 7.18 (1H, d, J=2.8 Hz), 7.24 (1H, dd, J=2.8, 8.8 Hz), 7.49(1H, d, J=2.8 Hz), 7.52 (1H, s), 7.84 (1H, s), 7.97 (1H, s), 8.00 (1H,s), 8.26 (1H, d, J=8.8 Hz), 8.65 (1H, d, J=5.2 Hz), 8.81 (1H, s).

Example 645N6-Methyl-7-(benzyloxy)-4-(3-chloro-(4-((methylamino)carbonyl)amino)phenoxy)-6-quinolinecarboxamide

The title compound (466 mg, 0.950 mmol, 81.6%) was obtained as lightbrown crystals from phenylN-(4-(7-(benzyloxy)-6-(methylamino)carbonyl-4-quinolyl)oxy-2-chlorophenyl)carbamate(645 mg, 1.16 mmol) and 2M methylamine-tetrahydrofuran solution, by thesame procedure as in Example 11.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.66 (3H, d, J=4.4 Hz), 2.81 (3H, d,J=4.4 Hz), 5.42 (2H, s), 6.51 (1H, d, J=5.2 Hz), 6.86 (1H, q, J=4.4 Hz),7.21 (1H, dd, J=2.8, 9.2 Hz), 7.30-7.45 (4H, m), 7.52-7.55 (3H, m), 8.10(1H, s), 8.22 (1H, d, J=9.2 Hz), 8.38 (1H, q, J=4.4 Hz), 8.49 (1H, s),8.62 (1H, d, J=5.2 Hz).

The starting materials were synthesized in the following manner.

Production Example 645-1 Phenyl4-(((2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)methyl)amino)-2-hydroxybenzoate

After adding Meldrum acid (29.2 g, 202 mmol), triethyl orthoformate (200ml) and isopropanol (200 ml) to phenyl 4-aminosalicylate (42.2 g, 184mmol), the mixture was heated and stirred at 100° C. for 1 hour. Afterallowing the reaction solution to cool to room temperature, it wasfurther stirred overnight. The precipitated crystals were filtered out,washed with isopropanol and diethyl ether and blow-dried to obtain thetitle compound (69.5 g, 181 mmol, 99%) as white crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.69 (6H, s), 7.21-7.28 (2H, m),7.29-7.36 (3H, m), 7.44-7.52 (2H, m), 8.04 (1H, d, J=8.4 Hz), 8.64 (1H,s), 10.52 (1H, br s), 11.24 (1H, br s).

Production Example 645-2 Phenyl7-(benzyloxy)-4-oxo-1,4-dihydro-6-quinolinecarboxylate

Phenyl4-(((2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)methyl)amino)-2-hydroxybenzoate(11.5 g, 0.030 mmol), benzyl bromide (5.64 g, 0.033 mmol) and potassiumcarbonate (4.56 g, 0.033 mmol) were stirred in dimethylformamide (45 ml)at 80° C. for 3 hours. The reaction solution was distributed between adiethyl ether-tetrahydrofuran mixed solvent and water, the organic layerwas washed with water and saturated brine and dried over anhydrousmagnesium sulfate, and the drying agent was filtered out and thefiltrate distilled off under reduced pressure. The obtained crudeproduct was suspended in ethanol, the suspension was diluted withhexane, and the crystals were filtered out, washed with hexane andblow-dried to obtain white crystals. The crystals were then heated andstirred for 1 hour in Dowtherm A (50 ml) at 200° C. After allowing thereaction solution to cool to room temperature, diethyl ether (25 ml) wasadded and the mixture was further stirred overnight. The precipitatedcrystals were filtered out, washed with diethyl ether and blow-dried toobtain the title compound (1.20 g, 3.23 mmol, 11%) as white crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 5.33 (2H, s), 6.03 (1H, d, J=7.4 Hz),7.19 (1H, s), 7.21-7.27 (2H, m), 7.28-7.36 (2H, m), 7.36-7.43 (2H, m),7.43-7.50 (2H, m), 7.52-7.58 (2H, m), 7.90 (1H, d, J=7.4 Hz), 8.71 (1H,s), 11.79 (1H, br s).

Production Example 645-3N6-Methyl-7-(benzyloxy)-4-chloro-6-quinolinecarboxamide

After adding thionyl chloride (12 ml) and a catalytic amount ofdimethylformamide to phenyl7-(benzyloxy)-4-oxo-1,4-dihydro-6-quinolinecarboxylate (1.20 g, 3.23mmol), the mixture was heated to reflux for 2 hours while stirring. Thereaction solution was concentrated under reduced pressure andazeotropically distilled twice with toluene, the residue was suspendedin dimethylformamide (20 ml), a 40% methylamine-methanol solution (5 ml)was gradually added while cooling in an ice water bath, and the mixturewas stirred for 1 hour. The reaction solution was distributed betweenethyl acetate-tetrahydrofuran (1:1) and water, and the organic layer waswashed with saturated aqueous ammonium chloride solution, water andsaturated brine and then dried over anhydrous sodium sulfate. Thesolvent was distilled off, diethyl ether and then hexane were added forcrystallization, and the crystals were filtered out and blow-dried toobtain the title compound (947 mg, 2.90 mmol, 89.7%) as light yellowcrystals.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 2.97 (3H, d, J=4.8 Hz), 5.35 (2H, s),7.40-7.52 (6H, m), 7.64 (1H, s), 7.91 (1H, m), 8.75 (1H, q, J=4.8 Hz),9.16 (1H, s).

Production Example 645-4N6-Methyl-4-(4-amino-3-chlorophenoxy)-7-(benzyloxy)-6-quinolinecarboxamide

After dissolving 4-amino-3-chlorophenol (624 mg, 4.35 mmol) indimethylsulfoxide (15 ml), sodium hydride (174 mg, 4.35 mmol) wasgradually added at room temperature and the mixture was stirred for 30minutes. N6-Methyl-7-(benzyloxy)-4-chloro-6-quinolinecarboxamide (947mg, 2.90 mmol) was added, and the mixture was heated at 100° C. whilestirring for 2 hours. After cooling to room temperature, the reactionsolution was distributed between ethyl acetate and water, and theorganic layer was washed with 1N aqueous sodium hydroxide, water andsaturated brine and dried over anhydrous sodium sulfate. The solvent wasdistilled off, the residue was suspended in ethyl acetate, thesuspension was diluted with hexane and the crystals were filtered outand blow-dried to obtain the title compound (1.098 g, 2.53 mmol, 87.3%)as light brown crystals.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 2.96 (3H, d, J=4.8 Hz), 4.10 (2H, m),5.35 (2H, s), 6.46 (1H, d, J=5.2 Hz), 6.84 (1H, d, J=8.8 Hz), 6.93 (1H,dd, J=2.8, 8.8 Hz), 7.14 (1H, d, J=2.8 Hz), 7.39-7.54 (5H, m), 7.58 (1H,s), 7.95 (1H, br), 8.62 (1H, d, J=5.2 Hz), 9.28 (1H, s).

Production Example 645-5 PhenylN-(4-(7-(benzyloxy)-6-(methylamino)carbonyl-4-quinolyl)oxy-2-chlorophenyl)carbamate

The title compound (1.291 g, 2.33 mmol, 92.1%) was obtained as lightbrown crystals fromN6-methyl-4-(4-amino-3-chlorophenoxy)-7-(benzyloxy)-6-quinolinecarboxamide(1.098 g, 2.53 mmol), in the same manner as Production Example 17.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 2.96 (3H, d, J=4.8 Hz), 5.35 (2H, s),6.50 (1H, d, J=5.2 Hz), 7.15 (1H, dd, J=2.8, 8.8 Hz), 7.19-7.30 (6H, m),7.40-7.52 (6H, m), 7.61 (1H, s), 7.95 (1H, m), 8.30 (1H, q, J=4.8 Hz),8.67 (1H, d, J=5.2 Hz), 9.27 (1H, s).

Example 646N6-Methyl-7-(benzyloxy)-4-(3-chloro-(4-((ethylamino)carbonyl)amino)phenoxy)-6-quinolinecarboxamide

The title compound (579 mg, 1.15 mmol, 98.4%) was obtained as lightbrown crystals from phenylN-(4-(7-(benzyloxy)-6-(methylamino)carbonyl-4-quinolyl)oxy-2-chlorophenyl)carbamate(645 mg, 1.16 mmol) and a 2 M ethylamine-tetrahydrofuran solution, bythe same procedure as in Example 11.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.06 (3H, t, J=7.2 Hz), 2.81 (3H, d,J=4.8 Hz), 3.11 (2H, m), 5.42 (2H, s), 6.51 (1H, d, J=5.2 Hz), 6.99 (1H,m), 7.19 (1H, dd, J=2.8, 9.2 Hz), 7.30-7.45 (4H, m), 7.52-7.55 (3H, m),8.06 (1H, s), 8.24 (1H, d, J=9.2 Hz), 8.38 (1H, q, J=4.8 Hz), 8.49 (1H,s), 8.62 (1H, d, J=5.2 Hz).

Example 647N6-Methyl-4-(3-chloro-4-(((methylamino)carbonyl)amino)phenoxy)-7-hydroxy-6-quinolinecarboxamide

The title compound (365.7 mg, 0.91 mmol, 96.1%) was obtained as yellowcrystals fromN6-methyl-7-(benzyloxy)-4-(3-chloro-4-(((methylamino)carbonyl)amino)phenoxy)-6-quinolinecarboxamide(466.3 mg, 0.95 mmol), by the same procedure as in Example 83.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.66 (3H, brs), 2.85 (3H, brs), 6.37(1H, m), 6.86 (1H, m), 7.10-7.30 (2H, m), 7.45 (1H, m), 8.09 (1H, brs),8.22 (1H, m), 8.56 (1H, m), 8.84 (1H, brs).

Example 648N6-Methyl-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-hydroxy-6-quinolinecarboxamide

The title compound (431.4 mg, 1.04 mmol, 90.8%) was obtained as lightyellow crystals fromN6-methyl-7-(benzyloxy)-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-6-quinolinecarboxamide(578.5 mg, 1.15 mmol), by the same procedure as in Example 83.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.06 (3H, t, J=7.2 Hz), 2.85 (3H,brs), 3.12 (2H, m), 6.36 (1H, m), 6.98 (1H, m), 7.20-7.24 (2H, m), 7.45(1H, d, J=2.8 Hz), 8.05 (1H, s), 8.25 (1H, d, J=9.2 Hz), 8.55 (1H, m),8.84 (1H, s).

Example 649 tert-Butyl4-(((4-(3-chloro-4-((methylamino)carbonyl)amino)phenoxy)-6-(methylaminocarbonyl)-7-quinolyl)oxy)methyl)-1-piperidinecarboxylate

The title compound (98.4 mg, 0.165 mmol, 55.0%) was obtained as lightbrown crystals fromN6-methyl-4-(3-chloro-4-(((methylamino)carbonyl)amino)phenoxy)-7-hydroxy-6-quinolinecarboxamide(120 mg, 0.299 mmol) and tert-butyl4-(bromomethyl)-1-piperidinecarboxylate), by the same procedure as inExample 7.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.17-1.33 (3H, m), 1.39 (9H, s), 1.75(2H, m), 2.06 (1H, m), 2.66 (3H, d, J=4.4 Hz), 2.77 (1H, m), 2.81 (3H,d, J=4.8 Hz), 3.97 (2H, m), 4.10 (2H, d, J=6.0 Hz), 6.51 (1H, d, J=5.2Hz), 6.85 (1H, q, J=4.4 Hz), 7.20 (1H, dd, J=2.8, 8.8 Hz), 7.44 (1H, d,J=2.8 Hz), 7.48 (1H, s), 8.10 (1H, s), 8.18 (1H, q, J=4.8 Hz), 8.22 (1H,d, J=8.8 Hz), 8.43 (1H, s), 8.63 (1H, d, J=5.2 Hz).

Example 650 tert-Butyl4-(((4-(3-chloro-4-((ethylamino)carbonyl)amino)phenoxy)-6-(methylaminocarbonyl)-7-quinolyl)oxy)methyl)-1-piperidinecarboxylate

The title compound (119.5 mg, 0.195 mmol, 56.6%) was obtained as lightbrown crystals fromN6-methyl-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-hydroxy-6-quinolinecarboxamide(143 mg, 0.345 mmol) and tert-butyl4-(bromomethyl)-1-piperidinecarboxylate, by the same procedure as inExample 7.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.06 (3H, t, J=7.2 Hz), 1.18-1.26(3H, m), 1.39 (9H, s), 1.76 (2H, m), 2.06 (1H, m), 2.77 (1H, m), 2.81(3H, d, J=4.8 Hz), 3.12 (2H, m), 3.98 (2H, m), 4.10 (2H, d, J=6.0 Hz),6.51 (1H, d, J=5.2 Hz), 6.97 (1H, m), 7.19 (1H, dd, J=2.8, 8.8 Hz), 7.44(1H, d, J=2.8 Hz), 7.48 (1H, s), 8.04 (1H, s), 8.18 (1H, q, J=4.8 Hz),8.24 (1H, d, J=8.8 Hz), 8.43 (1H, s), 8.63 (1H, d, J=5.2 Hz).

Example 651N6-Methyl-4-(3-chloro-4-(((methylamino)carbonyl)amino)phenoxy)-7-((1-methyl-4-piperidyl)methoxy)-6-quinolinecarboxamide

After adding trifluoroacetic acid (1 ml) to tert-butyl4-(((4-(3-chloro-4-((methylamino)carbonyl)amino)phenoxy)-6-(methylaminocarbonyl)-7-quinolyl)oxy)methyl)-1-piperidinecarboxylate(98.4 mg, 0.165 mmol) at room temperature, the mixture was stirred for 2hours. The reaction solution was concentrated under reduced pressure,and then the residue was dissolved in methanol, and triethylamine wasadded dropwise for neutralization. After distilling off the solvent, theresidue was dissolved in tetrahydrofuran (2 ml)—methanol (2 ml), andthen 37% aqueous formaldehyde (0.3 ml), acetic acid (0.05 ml) and sodiumcyanoborohydride (21 mg, 0.33 mmol) were added in that order at roomtemperature and the mixture was stirred for 30 minutes. The reactionsolution was distributed between ethyl acetate-tetrahydrofuran (1:1) andsaturated aqueous sodium bicarbonate, and the organic layer was washedwith saturated aqueous sodium bicarbonate and saturated brine and driedover anhydrous sodium sulfate. After distilling off the solvent, theresidue was subjected to silica gel column chromatography, and thetarget fraction was concentrated under reduced pressure and crystallizedwith ethyl acetate-hexane (1:5), after which the crystals were filteredout and blow-dried to obtain the title compound (64.2 mg, 0.125 mmol,76.2%) as white crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.34 (2H, m), 1.72-1.89 (5H, m), 2.15(3H, s), 2.66 (3H, d, J=4.4 Hz), 2.77-2.83 (5H, m), 4.08 (2H, d, J=6.4Hz), 6.51 (1H, d, J=5.2 Hz), 6.85 (1H, q, J=4.8 Hz), 7.20 (1H, dd,J=2.8, 8.8 Hz), 7.44 (1H, d, J=2.8 Hz), 7.48 (1H, s), 8.10 (1H, s), 8.20(1H, q, J=4.4 Hz), 8.22 (1H, d, J=8.8 Hz), 8.45 (1H, s), 8.63 (1H, d,J=5.2 Hz).

Example 652N6-Methyl-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-((1-methyl-4-piperidyl)methoxy)-6-quinolinecarboxamide

After adding trifluoroacetic acid (1 ml) to tert-butyl4-(((4-(3-chloro-4-((ethylamino)carbonyl)amino)phenoxy)-6-(methylaminocarbonyl)-7-quinolyl)oxy)methyl)-1-piperidinecarboxylate(119.5 mg, 0.195 mmol) at room temperature, the mixture was stirred for2 hours. The reaction solution was concentrated under reduced pressure,and then the residue was dissolved in methanol and triethylamine wasadded dropwise for neutralization. After distilling off the solvent, theresidue was dissolved in tetrahydrofuran (2 ml)—methanol (2 ml), andthen 37% aqueous formaldehyde (0.3 ml), acetic acid (0.05 ml) and sodiumcyanoborohydride (25 mg, 0.39 mmol) were added in that order at roomtemperature and the mixture was stirred for 30 minutes. The reactionsolution was distributed between ethyl acetate-tetrahydrofuran (1:1) andsaturated aqueous sodium bicarbonate, and the organic layer was washedwith saturated aqueous sodium bicarbonate and saturated brine and driedover anhydrous sodium sulfate. After distilling off the solvent, theresidue was subjected to silica gel column chromatography, and thetarget fraction was concentrated under reduced pressure and crystallizedwith ethyl acetate-hexane (1:5), after which the crystals were filteredout and blow-dried to obtain the title compound (78.3 mg, 0.149 mmol,76.2%) as white crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.06 (3H, t, J=7.2 Hz), 1.34 (2H, m),1.72-1.89 (5H, m), 2.15 (3H, s), 2.76-2.82 (5H, m), 3.12 (2H, m), 4.08(2H, d, J=6.4 Hz), 6.51 (1H, d, J=5.2 Hz), 6.97 (1H, m), 7.19 (1H, dd,J=2.8, 8.8 Hz), 7.44 (1H, d, J=2.8 Hz), 7.48 (1H, s), 8.04 (1H, s), 8.19(1H, q, J=4.4 Hz), 8.24 (1H, d, J=8.8 Hz), 8.45 (1H, s), 8.63 (1H, d,J=5.2 Hz).

Example 653N6-Methyl-4-(3-chloro-4-(((methylamino)carbonyl)amino)phenoxy)-7-((2R)-3-diethylamino-2-hydroxypropoxy)-6-quinolinecarboxamide

After adding (2R)oxiran-2-ylmethyl 4-methyl-1-benzenesulfonate (103 mg,0.499 mmol), potassium carbonate (50 mg, 0.359 mmol) anddimethylformamide (3 ml) toN6-methyl-4-(3-chloro-4-(((methylamino)carbonyl)amino)phenoxy)-7-hydroxy-6-quinolinecarboxamide(120 mg, 0.299 mmol), the mixture was stirred at 60° C. for 7 hours.Next, diethylamine (1.5 ml) was added and the mixture was furtherstirred overnight at 60° C. The reaction solution was distributedbetween ethyl acetate-tetrahydrofuran (1:1) and water, and the organiclayer was washed with water and saturated brine and then dried overanhydrous sodium sulfate. The solvent was distilled off, the residue wassubjected to silica gel column chromatography (eluent—ethylacetate:methanol=95:5), the fraction containing the target substance wasconcentrated, and crystals were precipitated from ethyl acetate-hexane(1:1), filtered out and blow-dried to obtain the title compound (71.8mg, 0.135 mmol, 45.2%) as white crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.95 (6H, t, J=7.2 Hz), 2.40-2.60(6H, m), 2.66 (3H, d, J=4.8 Hz), 2.85 (3H, d, J=4.8 Hz), 4.00 (1H, m),4.18 (1H, dd, J=6.0, 10.0 Hz), 4.32 (1H, dd, J=3.2, 10.0 Hz), 5.12 (1H,d, J=4.0 Hz), 6.52 (1H, d, J=5.2 Hz), 6.86 (1H, q, J=4.8 Hz), 7.22 (1H,dd, J=2.8, 9.2 Hz), 7.47 (1H, d, J=2.8 Hz), 7.53 (1H, s), 8.10 (1H, s),8.23 (1H, d, J=9.2 Hz), 8.50 (1H, q, J=4.8 Hz), 8.65 (1H, d, J=5.2 Hz),8.71 (1H, s).

Example 654N6-Methyl-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-((2R)-3-diethylamino-2-hydroxypropoxy)-6-quinolinecarboxamide

The title compound (92.4 mg, 0.170 mmol, 49.3%) was obtained as whitecrystals fromN6-methyl-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-hydroxy-6-quinolinecarboxamide(143 mg, 0.345 mmol), by the same procedure as in Example 653.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.95 (6H, t, J=7.2 Hz), 1.06 (3H, t,J=7.2 Hz), 2.40-2.60 (6H, m), 2.85 (3H, d, J=4.8 Hz), 3.12 (2H, m), 4.00(1H, m), 4.18 (1H, dd, J=6.0, 9.6 Hz), 4.32 (1H, dd, J=3.2, 9.6 Hz),5.12 (1H, d, J=4.4 Hz), 6.51 (1H, d, J=5.2 Hz), 6.98 (1H, m), 7.22 (1H,dd, J=2.8, 9.2 Hz), 7.47 (1H, d, J=2.8 Hz), 7.53 (1H, s), 8.05 (1H, s),8.25 (1H, d, J=9.2 Hz), 8.50 (1H, q, J=4.8 Hz), 8.65 (1H, d, J=5.2 Hz),8.72 (1H, s).

Example 655N6-Methyl-4-(3-chloro-4-(((methylamino)carbonyl)amino)phenoxy)-7-((2R)-2-hydroxy-3-(1-pyrrolidino)propoxy)-6-quinolinecarboxamide

After adding (2R)oxiran-2-ylmethyl 4-methyl-1-benzenesulfonate (103 mg,0.499 mmol), potassium carbonate (50 mg, 0.359 mmol) anddimethylformamide (3 ml) toN6-methyl-4-(3-chloro-4-(((methylamino)carbonyl)amino)phenoxy)-7-hydroxy-6-quinolinecarboxamide(120 mg, 0.299 mmol), the mixture was stirred at 60° C. for 7 hours.After allowing the reaction solution to cool to room temperature,pyrrolidine (0.5 ml) was added and the mixture was further stirredovernight. The reaction solution was distributed between ethylacetate-tetrahydrofuran (1:1) and water, and the organic layer waswashed with water and saturated brine and then dried over anhydroussodium sulfate. The solvent was distilled off, the residue was subjectedto silica gel column chromatography (eluent-ethylacetate:methanol=95:5), the fraction containing the target substance wasconcentrated, and crystals were precipitated from ethyl acetate-hexane(1:1), filtered out and blow-dried to obtain the title compound (79.3mg, 0.150 mmol, 50.2%) as white crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.67 (4H, m), 2.40-2.60 (5H, m),2.64-2.69 (4H, m), 2.85 (3H, d, J=4.8 Hz), 4.06 (1H, m), 4.17 (1H, m),4.33 (1H, dd, J=3.6, 10.4 Hz), 5.23 (1H, d, J=4.8 Hz), 6.52 (1H, d,J=5.2 Hz), 6.86 (1H, q, J=4.8 Hz), 7.22 (1H, dd, J=2.8, 9.2 Hz), 7.47(1H, d, J=2.8 Hz), 7.54 (1H, s), 8.10 (1H, s), 8.23 (1H, d, J=9.2 Hz),8.50 (1H, q, J=4.8 Hz), 8.65 (1H, d, J=5.2 Hz), 8.71 (1H, s).

Example 656N6-Methyl-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-((2R)-2-hydroxy-3-(1-pyrrolidino)propoxy)-6-quinolinecarboxamide

The title compound (94.8 mg, 0.175 mmol, 50.7%) was obtained as whitecrystals fromN6-methyl-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-hydroxy-6-quinolinecarboxamide(143 mg, 0.345 mmol), by the same procedure as in Example 655.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.06 (3H, t, J=7.2 Hz), 1.67 (4H, m),2.40-2.60 (5H, m), 2.66 (1H, dd, J=6.4, 12.4 Hz), 2.85 (3H, d, J=4.8Hz), 3.12 (2H, m), 4.06 (1H, m), 4.16 (1H, dd, J=6.0, 10.0 Hz), 4.33(1H, dd, J=3.2, 10.0 Hz), 5.23 (1H, d, J=5.2 Hz), 6.51 (1H, d, J=5.2Hz), 6.98 (1H, m), 7.21 (1H, dd, J=2.8, 8.8 Hz), 7.47 (1H, d, J=2.8 Hz),7.53 (1H, s), 8.05 (1H, s), 8.25 (1H, d, J=8.8 Hz), 8.50 (1H, q, J=4.8Hz), 8.65 (1H, d, J=5.2 Hz), 8.71 (1H, s).

Example 657N-Cyclopropyl-N′-(4-(6-(4-(2-diethylaminoethoxy)-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)-2-fluorophenyl)urea

After dissolving 65 mg ofN-cyclopropyl-N′-(4-(6-(4-(2-diethylaminoethoxy)-phenyl)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)-2-fluorophenyl)ureain 2 ml of tetrahydrofuran, there was added dropwise 0.5 ml oftetrabutylammonium fluoride (1M tetrahydrofuran solution) and themixture was refluxed for 3 hours. After returning it to roomtemperature, water was added, the mixture was stirred, and theprecipitated crystals were filtered out, washed with water andether-hexane (1:1) and dried under reduced pressure to obtain 25 mg ofthe title compound.

MS Spectrum (ESI): 519 (M+1),

¹H-NMR Spectrum: (DMSOd₆)0.38-0.43 (2H, m), 0.62-0.68 (2H, m), 0.99 (6H,t, J=7.3 Hz) 2.53-2.61 (5H, m), 2.80 (2H, t, J=6.9 Hz), 4.08 (2H, t,J=6.9 Hz), 6.79-6.84 (1H, m), 6.91 (1H, s), 7.01-7.07 (3H, m), 7.26 (1H,dd, J=2.9, 11.2 Hz), 7.88 (2H, d, J=9.0 Hz), 8.05-8.16 (1H, m), 8.18(1H, brs), 8.28 (1H, s), 12.68 (1H, brs)

The intermediates were synthesized in the following manner.

Production Example 657-16-(4-Benzyloxyphenyl)-4-(3-fluoro-4-nitrophenoxy)-7-(trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine

After adding 248 mg of 3-fluoro-4-nitrophenol, 0.208 ml of 2,6-lutidineand 1 ml of N-methylpyrrolidine to 490 mg of6-(4-benzyloxyphenyl)-4-chloro-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine,the mixture was stirred at 130° C. for 24 hours. After returning it toroom temperature, water was added, liquid separation and extraction wereperformed with an ethyl acetate-tetrahydrofuran mixed solvent, and theorganic layer was washed with saturated brine, dried over sodiumsulfate, concentrated and subjected to NH silica gel columnchromatography (ethyl acetate) to obtain 472 mg of the title compound.

1H-NMR Spectrum: (DMSOd6) −0.08 (9H, s), 0.87 (2H, t, J=7.4 Hz), 3.63(2H, t, J=7.4 Hz), 5.20 (2H, s), 5.61 (2H, s), 6.83 (1H, s), 7.00-7.80(11H, m), 8.30 (1H, t, J=8.6 Hz), 8.40 (1H, s).

Production Example 657-24-(6-(4-Benzyloxyphenyl)-7-(trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)-2-fluorophenylamine

After adding 400 mg of iron powder, 1 g of ammonium chloride, 20 ml ofethanol, 10 ml of tetrahydrofuran and 10 ml of water to 470 mg of6-(4-benzyloxyphenyl)-4-(3-fluoro-4-nitrophenoxy)-7-(trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine,the mixture was stirred at 85° C. for 3 hours. After returning it toroom temperature, it was filtered with celite, and ethyl acetate andwater were added to the filtrate for liquid separation and extraction.The organic layer was washed with saturated brine, dried over anhydroussodium sulfate, filtered with plug cotton, concentrated and subjected toNH silica gel column chromatography (hexane-ethyl acetate) to obtain 263mg of the title compound.

MS Spectrum (ESI): 557 (M+1).

¹H-NMR Spectrum: (DMSOd₆)-0.09 (9H, s), 0.85 (2H, t, J=8.9 Hz), 3.61(2H, t, J=8.9 Hz), 5.09-5.13 (2H, m), 5.19 (2H, s), 5.59 (2H, s), 6.60(1H, s), 6.79-6.73 (2H, m), 7.03 (1H, d, J=11.5 Hz), 7.16 (2H, d, J=9.6Hz), 7.32-7.50 (5H, m), 7.70 (2H, d, J=9.6 Hz), 8.40 (1H, s).

Production Example 657-3N-(4-(6-(4-Benzyloxyphenyl)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)-2-fluorophenyl)-N′-cyclopropylurea

After dissolving 261 mg of4-[6-(4-benzyloxyphenyl)-7-(trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]-2-fluorophenylaminein 3 ml of dimethylformamide, 0.053 ml of pyridine and 0.082 ml ofphenyl chlorocarbonate were added, the mixture was stirred at roomtemperature for 2 hours, 0.081 ml of cyclopropylamine was added and themixture was further stirred overnight. Water was added, liquidseparation and extraction were performed with ethyl acetate, and theorganic layer was washed with saturated brine, dried over sodiumsulfate, concentrated and subjected to silica gel column chromatography(hexane-ethyl acetate) to obtain 265 mg of the title compound.

¹H-NMR Spectrum: (DMSOd₆)-0.09 (9H, s), 0.38-0.43 (2H, m), 0.60-0.70(2H, m), 0.87 (2H, t, J=7.5 Hz), 2.50-2.60 (1H, m), 3.61 (2H, t, J=7.5Hz), 5.20 (2H, s), 5.60 (2H, s), 6.61 (1H, s), 6.68-6.72 (1H, m), 7.04(1H, d, J=8.3 Hz), 7.18 (2H, d, J=9.0 Hz), 7.28 (1H, dd, J=3.4, 11.7Hz), 7.32-7.53 (5H, m), 7.72 (2H, d, J=9.0 Hz), 8.10 (1H, t, J=8.2 Hz),8.18 (1H, brs), 8.40 (1H, s).

Production Example 657-4N-Cyclopropyl-N′-(2-fluoro-4-(6-(4-hydroxyphenyl)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl)urea

After dissolving 263 mg of1-(4-(6-(4-benzyloxyphenyl)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)-2-fluorophenyl)-3-cyclopropylureain 7 ml of ethanol and 3 ml of tetrahydrofuran, 30 mg of platinum oxidewas added and the mixture was stirred overnight at room temperature andordinary pressure under a hydrogen atmosphere, after which it wasfiltered with celite and concentrated under reduced pressure. Theresidue was subjected to silica gel column chromatography (hexane-ethylacetate) to obtain 160 mg of the title compound.

¹H-NMR Spectrum: (DMSOd₆)-0.08 (9H, s), 0.39-0.43 (2H, m), 0.61-0.68(2H, m), 0.86 (2H, t, J=7.5 Hz), 2.50-2.60 (1H, m), 3.61 (2H, t, J=7.5Hz), 5.58 (2H, s), 6.63 (1H, s), 6.78-6.82 (1H, m), 6.90 (2H, d, J=8.6Hz), 7.01-7.07 (1H, m,), 7.28 (1H, dd, J=3.3, 11.9 Hz), 7.60 (2H, d,J=8.6 Hz), 8.06-8.13 (1H, m,), 8.19 (1H, brs), 8.40 (1H, s).

Production Example 657-5N-Cyclopropyl-N′-(4-(6-(4-(2-diethylaminoethoxy)-phenyl)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)-2-fluorophenyl)urea

After dissolving 100 mg ofN-cyclopropyl-N′-(2-fluoro-4-(6-(4-hydroxyphenyl)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)-2-phenyl)ureain 1 ml of dimethylformamide, 110 mg of 2-chloroethyldiethylaminehydrochloride and 126 mg of potassium carbonate were added and themixture was stirred at 80° C. for 15 hours. The mixture was thenreturned to room temperature, water was added, and liquid separation andextraction were performed with an ethyl acetate-tetrahydrofuran mixedsolvent. The organic layer was washed with saturated brine, dried oversodium sulfate, concentrated and subjected to NH silica gel columnchromatography (hexane-ethyl acetate) to obtain 67 mg of the titlecompound.

MS Spectrum (ESI): 649 (M+1).

Example 658N-Cyclopropyl-N′-(2-fluoro-4-(6-(4-((2R)-2-hydroxy-3-pyrrolidin-1-ylpropoxy)-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)-phenyl)urea

The title compound (30 mg) was obtained from 63 mg ofN-cyclopropyl-N′-(2-fluoro-4-(6-(4-((2R)-2-hydroxy-3-pyrrolidinopropoxy)phenyl)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)-phenyl)urea,by the same procedure as in Example 657.

MS Spectrum (ESI): 547 (M+1),

¹H-NMR Spectrum: (DMSOd₆) 0.38-0.43 (2H, m), 0.60-0.69 (2H, m),1.65-1.72 (4H, m), 2.45-2.70 (7H, m, covered by DMSO peak), 3.90-4.10(3H, m), 4.96 (1H, brs) 6.91 (1H, s), 6.76-6.80 (1H, m), 7.01-7.07 (3H,m), 7.26 (1H, dd, J=10.9, 2.4 Hz), 7.88 (2H, d, J=9.1 Hz), 8.06-8.14(1H, m,), 8.15 (1H, brs,), 8.28 (1H, s,) 12.60 (1H, brs)

The intermediate was synthesized in the following manner.

Production Example 658-1N-Cyclopropyl-N′-(2-fluoro-4-(6-(4-((2R)-2-hydroxy-3-pyrrolidinopropoxy)phenyl)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl)urea

After dissolvingN-cyclopropyl-N′-(2-fluoro-4-(6-(4-hydroxyphenyl)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl)urea(89 mg) in dimethylformamide (2 ml), there were added (2R)-(−)-glycidylp-toluenesulfonate (111 mg, 3 equivalents) and potassium carbonate (112mg, 5 equivalents), and the mixture was stirred overnight at 65° C. Itwas then returned to room temperature and stationed, and the supernatantwas decanted (1.8 ml portion of dimethylformamide). After adding 0.1 mlof pyrrolidine thereto, the mixture was stirred at 65° C. for 3 hours.Water was then added and liquid separation and extraction were performedwith ethyl acetate-tetrahydrofuran. The organic layer was concentratedand subjected to NH silica gel column chromatography (hexane-ethylacetate) to obtain 63 mg of the title compound.

MS Spectrum (ESI): 677 (M+1).

Example 659N-Cyclopropyl-N′-(4-(6-(4-(3-diethylamino-(2R)-2-hydroxypropoxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)-2-fluorophenyl)urea

The title compound (1 mg) was obtained from 5 mg ofN-cyclopropyl-N′-(4-(6-(4-(3-diethylamino-(2R)-2-hydroxypropoxy)-phenyl])-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)-2-fluorophenyl)urea,by the same procedure as in Example 657.

MS Spectrum (ESI): 549 (M+1).

The intermediate was synthesized in the following manner.

Production Example 659-1N-Cyclopropyl-N′-(4-(6-(4-(3-diethylamino-(2R)-2-hydroxypropoxy)-phenyl))-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)-2-fluorophenyl)urea

After dissolvingN-cyclopropyl-N′-(2-fluoro-4-(6-(4-hydroxyphenyl)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)-2-phenyl)urea(89 mg) in dimethylformamide (2 ml), there were added (2R)-(−)-glycidylp-toluenesulfonate (111 mg, 3 equivalents) and potassium carbonate (112mg, 5 equivalents), and the mixture was stirred overnight at 65° C. Itwas then returned to room temperature and stationed, and the supernatantwas decanted (0.2 ml portion of dimethylformamide). After adding 1 ml oftetrahydrofuran and 0.4 ml of diethylamine thereto, the mixture wasstirred at 65° C. for 30 minutes. Water was then added and liquidseparation and extraction were performed with ethylacetate-tetrahydrofuran. The organic layer was concentrated andsubjected to NH silica gel column chromatography (hexane-ethyl acetate)to obtain 5 mg of the title compound.

MS Spectrum (ESI): 679 (M+1).

Example 6607-(Benzyloxy)-4-(3-chloro-(4-((cyclopropylamino)carbonyl)amino)phenoxy)-6-quinolinecarboxylicacid

After adding methanol (30 ml) and a 2N sodium hydroxide aqueous solution(10 ml) to methyl7-(benzyloxy)-4-(3-chloro-(4-((cyclopropylamino)carbonyl)amino)phenoxy)-6-quinolinecarboxylate(2.218 g, 4.28 mmol), the mixture was stirred at 60° C. for 1 hour. Thereaction solution was allowed to cool to room temperature, and afterneutralization by addition of 1N hydrochloric acid, the methanol wasdistilled off and the precipitated light brown crystals were filteredout, thoroughly washed with water and dried at 70° C. to obtain thetitle compound (2.121 g, 4.21 mmol, 98.3%).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.43 (2H, m), 0.67 (2H, m), 2.57 (1H,m), 5.40 (2H, s), 6.56 (1H, d, J=5.2 Hz), 7.21 (1H, d, J=2.8 Hz), 7.26(1H, dd, J=2.8, 8.8 Hz), 7.32-7.44 (3H, m), 7.51 (1H, d, J=2.8 Hz), 7.56(2H, d, J=6.8 Hz), 7.60 (1H, s), 8.00 (1H, s), 8.28 (1H, dd, J=2.8, 8.8Hz), 8.57 (1H, s), 8.69 (1H, d, J=5.2 Hz).

Example 661N6-Methyl-7-(benzyloxy)-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-6-quinolinecarboxamide

After dissolving7-(benzyloxy)-4-(3-chloro-(4-((cyclopropylamino)carbonyl)amino)phenoxy)-6-quinolinecarboxylicacid (1.056 g, 2.10 mmol) in dimethylformamide (10 ml) under a nitrogenatmosphere, there were added a 40% methylamine-methanol solution (2 ml),triethylamine (1 ml) and(1H-1,2,3-benzotriazol-1-yloxy)(tri(dimethylamino))phosphoniumhexafluorophosphate(1.11 g, 2.52 mmol) in that order at room temperature, and the mixturewas stirred for 6 hours. Water was added to the reaction solution toprecipitate crystals, and these were filtered out, washed thoroughlywith water and dried at 70° C. to obtain the title compound (988 mg,1.91 mmol, 91.2%) as white crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.42 (2H, m), 0.65 (2H, m), 2.56 (1H,m), 2.82 (3H, d, J=4.4 Hz), 5.42 (2H, s), 6.51 (1H, d, J=5.2 Hz), 7.18(1H, d, J=2.8 Hz), 7.21 (1H, dd, J=2.8, 8.8 Hz), 7.30-7.55 (7H, m), 7.96(1H, s), 8.25 (1H, d, J=8.8 Hz), 8.38 (1H, q, J=4.4 Hz), 8.49 (1H, s),8.62 (1H, d, J=5.2 Hz).

Example 662N6-Ethyl-7-(benzyloxy)-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-6-quinolinecarboxamide

The title compound (1.022 g, 1.92 mmol, 91.8%) was obtained as whitecrystals from7-(benzyloxy)-4-(3-chloro-(4-((cyclopropylamino)carbonyl)amino)phenoxy)-6-quinolinecarboxylicacid (1.056 g, 2.10 mmol) and 2M ethylamine-tetrahydrofuran solution, bythe same procedure as in Example 661.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.42 (2H, m), 0.65 (2H, m), 1.04 (3H,t, J=7.2 Hz), 2.56 (1H, m), 3.25-3.31 (2H, m), 5.39 (2H, s), 6.52 (1H,d, J=5.2 Hz), 7.18 (1H, d, J=2.8 Hz), 7.22 (1H, dd, J=2.8, 8.8 Hz),7.32-7.44 (3H, m), 7.47 (1H, d, J=2.8 Hz), 7.56 (2H, d, J=7.2 Hz), 7.59(1H, s), 7.97 (1H, s), 8.26 (1H, d, J=8.8 Hz), 8.34 (1H, t, J=7.2 Hz),8.49 (1H, s), 8.64 (1H, d, J=5.2 Hz).

Example 663N6-Methyl-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-hydroxy-6-quinolinecarboxamide

The title compound (811 mg, 1.90 mmol, quantitative) was obtained aslight yellow crystals fromN6-methyl-7-(benzyloxy)-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-6-quinolinecarboxamide)(983 mg, 1.90 mmol), by the same procedure as in Example 83.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.42 (2H, m), 0.65 (2H, m), 2.56 (1H,m), 2.85 (3H, s), 6.32 (1H, br), 7.18-7.24 (4H, m), 7.45 (1H, s), 7.96(1H, s), 8.25 (1H, d, J=9.2 Hz), 8.51 (1H, m), 8.81 (1H, s).

Example 664N6-Ethyl-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-hydroxy-6-quinolinecarboxamide

The title compound (845 mg, 1.91 mmol, quantitative) was obtained aslight yellow crystals fromN6-ethyl-7-(benzyloxy)-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-6-quinolinecarboxamide)(1.016 g, 1.91 mmol), by the same procedure as in Example 83.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.42 (2H, m), 0.65 (2H, m), 1.16 (3H,t, J=7.2 Hz), 2.56 (1H, m), 3.36 (2H, m), 6.41 (1H, d, J=5.2 Hz),7.15-7.35 (4H, m), 7.49 (1H, d, J=2.4 Hz), 7.97 (1H, s), 8.27 (1H, dd,J=4.0, 9.2 Hz), 8.60 (1H, d, J=5.2 Hz), 8.88 (1H, s), 12.68 (1H, br).

Example 665N6-Methyl-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-(3-(1-pyrrolidino)propoxy)-6-quinolinecarboxamide

The title compound (78.4 mg, 0.146 mmol, 29.1%) was obtained as lightyellow crystals fromN6-methyl-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-hydroxy-6-quinolinecarboxamide(213.4 mg, 0.50 mmol) and 1-(3-chloropropyl)pyrrolidine hydrochloride,by the same procedure as in Example 7.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.42 (2H, m), 0.65 (2H, m), 1.68 (4H,m), 1.99 (2H, m), 2.44 (4H, m), 2.54-2.59 (3H, m), 2.83 (3H, d, J=4.8Hz), 4.28 (2H, m), 6.51 (1H, d, J=5.2 Hz), 7.18 (1H, d, J=2.8 Hz), 7.22(1H, dd, J=2.8, 8.8 Hz), 7.47 (1H, d, J=2.8 Hz), 7.49 (1H, s), 7.96 (1H,s), 8.24-8.27 (2H, m), 8.53 (1H, s), 8.64 (1H, d, J=5.2 Hz).

Example 666N6-Ethyl-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-(3-(1-pyrrolidino)propoxy)-6-quinolinecarboxamide

The title compound (85.0 mg, 0.154 mmol, 30.8%) was obtained as lightyellow crystals fromN6-ethyl-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-hydroxy-6-quinolinecarboxamide(213.4 mg, 0.50 mmol) and 1-(3-chloropropyl)pyrrolidine hydrochloride,by the same procedure as in Example 7.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.42 (2H, m), 0.65 (2H, m), 1.16 (3H,t, J=7.2 Hz), 1.68 (4H, m), 2.00 (2H, m), 2.44 (4H, m), 2.53-2.60 (3H,m), 3.32-3.36 (2H, m), 4.27 (2H, m), 6.51 (1H, d, J=5.2 Hz), 7.18 (1H,d, J=2.8 Hz), 7.22 (1H, dd, J=2.8, 9.2 Hz), 7.47 (1H, d, J=2.8 Hz), 7.48(1H, s), 7.96 (1H, s), 8.24-8.27 (2H, m), 8.51 (1H, s), 8.64 (1H, d,J=5.2 Hz).

Example 667N6-Methyl-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-((2R)oxiran-2-yl)methoxy-6-quinolinecarboxamide

The title compound (230.0 mg, 0.476 mmol, 47.6%) was obtained as lightyellow crystals fromN6-methyl-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-hydroxy-6-quinolinecarboxamide(426.9 mg, 1.00 mmol) and (2R)oxiran-2-ylmethyl4-methyl-1-benzenesulfonate, by the same procedure as in Example 7.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.42 (2H, m), 0.65 (2H, m), 2.56 (1H,m), 2.79-2.90 (2H, m), 2.84 (3H, d, J=4.4 Hz), 3.47 (1H, m), 4.16 (1H,dd, J=6.0, 11.6 Hz), 4.63 (1H, dd, J=2.4, 11.6 Hz), 6.52 (1H, d, J=5.2Hz), 7.18 (1H, d, J=2.8 Hz), 7.22 (1H, dd, J=2.8, 8.8 Hz), 7.47 (1H, d,J=2.8 Hz), 7.54 (1H, s), 7.97 (1H, s), 8.24-8.28 (2H, m), 8.53 (1H, s),8.65 (1H, d, J=5.2 Hz).

Example 668N6-Ethyl-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-((2R)oxiran-2-yl)methoxy-6-quinolinecarboxamide

The title compound (235.4 mg, 0.474 mmol, 47.4%) was obtained as lightyellow crystals fromN6-ethyl-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-hydroxy-6-quinolinecarboxamide)(440.9 mg, 1.00 mmol) and (2R)oxiran-2-ylmethyl4-methyl-1-benzenesulfonate, by the same procedure as in Example 7.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.42 (2H, m), 0.65 (2H, m), 1.15 (3H,t, J=7.2 Hz), 2.56 (1H, m), 2.82 (1H, m), 2.89 (1H, m), 3.28-3.36 (2H,m), 3.48 (1H, m), 4.17 (1H, dd, J=2.0, 11.2 Hz), 4.62 (1H, dd, J=2.4,11.2 Hz), 6.52 (1H, d, J=5.2 Hz), 7.18 (1H, d, J=2.8 Hz), 7.22 (1H, dd,J=2.8, 9.2 Hz), 7.47 (1H, d, J=2.8 Hz), 7.53 (1H, s), 7.97 (1H, s),8.24-8.30 (2H, m), 8.52 (1H, s), 8.65 (1H, d, J=5.2 Hz).

Example 669N6-Methyl-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-((2R)-2-hydroxy-3-(1-pyrrolidino)propoxy-6-quinolinecarboxamide

After dissolvingN6-methyl-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-((2R)oxiran-2-yl)methoxy-6-quinolinecarboxamide(225 mg, 0.466 mmol) in tetrahydrofuran (5.0 ml) under a nitrogenatmosphere, pyrrolidine (1.0 ml) was added and the mixture was stirredovernight at room temperature. The reaction solution was concentratedunder reduced pressure, the residue was subjected to silica gel columnchromatography (eluent-ethyl acetate:methanol=95:5), the fractioncontaining the target substance was concentrated, and crystalsprecipitated from ethyl acetate were filtered out and blow-dried toobtain the title compound (164.5 mg, 0.297 mmol, 63.7%) as light yellowcrystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.42 (2H, m), 0.65 (2H, m), 1.67 (4H,m), 2.48-2.59 (6H, m), 2.66 (1H, dd, J=6.4, 12.0 Hz), 2.85 (3H, d, J=4.8Hz), 4.05 (1H, m), 4.16 (1H, dd, J=6.0, 10.0 Hz), 4.34 (1H, dd, J=3.2,10.0 Hz), 5.24 (1H, d, J=4.8 Hz), 6.51 (1H, d, J=5.2 Hz), 7.18-7.25 (2H,m), 7.48 (1H, d, J=2.8 Hz), 7.54 (1H, s), 7.97 (1H, s), 8.26 (1H, d,J=9.2 Hz), 8.50 (1H, q, J=4.8 Hz), 8.65 (1H, d, J=5.2 Hz), 8.71 (1H, s).

Example 670N6-Ethyl-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-((2R)-2-hydroxy-3-(1-pyrrolidino)propoxy)-6-quinolinecarboxamide

The title compound (146.0 mg, 0.257 mmol, 55.5%) was obtained as lightyellow crystals fromN6-ethyl-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-((2R)oxiran-2-yl)methoxy-6-quinolinecarboxamide)(230 mg, 0.463 mmol), by the same procedure as in Example 669.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.42 (2H, m), 0.65 (2H, m), 1.16 (3H,t, J=7.2 Hz), 1.67 (4H, m), 2.47-2.58 (6H, m), 2.68 (1H, dd, J=6.8, 12.0Hz), 3.30-3.40 (2H, m), 4.04 (1H, m), 4.19 (1H, dd, J=5.6, 9.6 Hz), 4.33(1H, dd, J=3.2, 9.6 Hz), 5.18 (1H, d, J=4.8 Hz), 6.51 (1H, d, J=5.2 Hz),7.18-7.25 (2H, m), 7.48 (1H, d, J=2.8 Hz), 7.52 (1H, s), 7.97 (1H, s),8.26 (1H, d, J=9.2 Hz), 8.53 (1H, m), 8.65 (1H, d, J=5.2 Hz), 8.71 (1H,s).

Example 670-1N-(4-((6-Cyano-7-((1-methyl-4-piperidyl)methoxy]-4-quinolyl)oxy)-2-fluorophenyl)-N′-cyclopropylurea

After suspending 320 mg ofN-(4-((6-cyano-7-(4-piperidylmethoxy)-4-quinolyl)oxy)-2-fluorophenyl)-N′-cyclopropylureain 20 ml of tetrahydrofuran, there were added 1 ml of formaldehyde (37%aqueous solution), 80 mg of acetic acid and 280 mg of sodiumtriacetoxyborohydride while stirring at room temperature. After stirringfor 20 minutes, a 2N aqueous sodium hydroxide solution and ethyl acetatewere added for extraction. The extract was passed through a glass filtercoated with NH type silica gel, and the silica gel was thoroughly washedwith an ethyl acetate:methanol=20:1 mixed solvent. The organic solventswere combined and distilled off under reduced pressure. Ethyl acetatewas added to the residue, and the mixture was filtered to obtain 130 mgof a light yellow solid.

¹H-NMR (DMSO-d₆) δ (ppm): 0.35-0.45 (2H, m), 0.59-0.69 (2H, m),1.32-1.46 (2H, m), 1.71-1.89 (5H, m), 2.14 (3H, s), 2.49-2.59 (1H, m),2.74-2.84 (2H, m), 4.12 (2H, d, J=5.2 Hz), 6.56 (1H, d, J=5.2 Hz), 6.80(1H, s), 7.07 (1H, d, J=9.2 Hz), 7.31 (1H, d, J=11.2 Hz), 7.55 (1H, s),8.16-8.27 (2H, m), 8.69 (1H, s), 8.70 (1H, d, J=5.2 Hz).

The intermediates were obtained in the following manner.

Production Example 670-1-1 tert-Butyl4-(((4-(4-amino-3-fluorophenoxy)-6-cyano-7-quinolyl)oxy)methyl)-1-piperidinecarboxylate

4-(4-Amino-3-fluorophenoxy)-7-hydroxy-6-quinoline carbonitrile (500 mg),tert-butyl 4-(bromomethyl)-1-piperidinecarboxylate (550 mg), potassiumcarbonate (700 mg) and dimethylformamide (5 ml) were stirred together at60° c. for 2 hours. Water and ethyl acetate were added for extraction,and the extract was dried over magnesium sulfate. The drying agent wasfiltered out, and silica gel was added to the filtrate which was thendistilled off under reduced pressure for adsorption. The reactionsolution-adsorbed silica gel was subjected to column chromatography(hexane:ethyl acetate=1:1, followed by 1:2, 1:3, ethyl acetate) in a drycolumn packed with silica gel, to obtain 423 mg of a brown oil.

¹H-NMR (DMSO-d₆) δ (ppm): 1.20-1.32 (2H, m), 1.39 (9H, s), 1.75-1.83(2H, m), 1.98-2.10 (1H, m), 2.67-2.88 (2H, m), 3.94-4.05 (2H, m), 4.15(2H, d, J=6.4 Hz), 5.25 (2H, bs), 6.51 (1H, d, J=5.2 Hz), 6.83-6.88 (2H,m), 7.06-7.7.11 (1H, m), 7.55 (1H, s), 8.69 (1H, s), 8.70 (1H, d, J=5.2Hz).

Production Example 670-1-2 tert-Butyl4-(((6-cyano-4-(3-fluoro-4-((phenoxycarbonyl)amino)phenoxy)-7-quinolyl)oxy)methyl)-1-piperidinecarboxylate

tert-Butyl4-(((4-(4-amino-3-fluorophenoxy)-6-cyano-7-quinolyl)oxy)methyl)-1-piperidinecarboxylate(523 mg), pyridine (0.17 ml) and tetrahydrofuran (10 ml) were stirredwhile cooling on ice, and then phenyl chloroformate was added dropwise.Immediately after completion of the dropwise addition, the cooling bathwas removed and the mixture was returned to room temperature. After 15minutes of stirring, water and ethyl acetate were added for extraction.Silica gel was added to the extract and the solvent was distilled offunder reduced pressure for adsorption. The reaction solution-adsorbedsilica gel was purified by column chromatography (hexane:ethylacetate=1:1, followed by 1:2, ethyl acetate) in a dry column packed withsilica gel, to obtain 490 mg of a yellow powder.

¹H-NMR (DMSO-d₆) δ (ppm): 1.20-1.32 (2H, m), 1.39 (9H, s), 1.75-1.83(2H, m), 1.98-2.10 (1H, m), 2.70-2.85 (2H, m), 3.95-4.04 (2H, m), 4.16(2H, d, J=6.0 Hz), 6.64 (1H, d, J=5.2 Hz), 7.16-7.28 (4H, m), 7.38-7.46(3H, m), 7.59 (1H, s), 7.80 (1H, dd, J=8.8 Hz, 8.8 Hz), 8.72 (1H, s),8.75 (1H, d, J=5.2 Hz), 10.02 (1H, brs).

Production Example 670-1-3 tert-Butyl4-(((6-cyano-4-(4-(((cyclopropylamino)carbonyl)amino)-3-fluorophenoxy)-7-quinolyl)oxy)methyl)-1-piperidinecarboxylate

tert-Butyl4-(((6-cyano-4-(3-fluoro-4-((phenoxycarbonyl)amino)phenoxy)-7-quinolyl)oxy)methyl)-1-piperidinecarboxylate(490 mg), cyclopropylamine (0.72 ml) and tetrahydrofuran (5 ml) werestirred together at 60° C. for 35 minutes. Silica gel was added to thereaction solution and the solvent was distilled off under reducedpressure for adsorption. The reaction solution-adsorbed silica gel waspurified by column chromatography (ethyl acetate, followed by ethylacetate:methanol=20:1) in a dry column packed with silica gel, to obtain340 mg of a light yellow solid.

¹H-NMR (DMSO-d₆) δ (ppm): 0.37-0.44 (2H, m), 0.59-0.69 (2H, m),1.29-1.32 (2H, m), 1.39 (9H, s), 1.77-1.84 (2H, m), 1.99-2.11 (1H, m),2.39-2.59 (1H, m), 2.59-2.87 (2H, m), 3.96-4.04 (2H, m), 4.16 (2H, d,J=6.4 Hz), 6.57 (1H, d, J=5.2 Hz), 6.80 (1H, d, J=2.8 Hz), 7.05-7.11(1H, m), 7.31 (1H, dd, J=12.0 Hz, 2.8 Hz), 7.58 (1H, s), 8.19-8.27 (2H,m), 8.71 (1H, s), 8.73 (1H, d, J=5.2 Hz)

Production Example 670-1-4N-(4-((6-Cyano-7-(4-piperidylmethoxy)-4-quinolyl)oxy)-2-fluorophenyl)-N′-cyclopropylurea

After adding 5 ml of trifluoroacetic acid to 340 mg of tert-butyl4-(((6-cyano-4-(4-(((cyclopropylamino)carbonyl)amino)-3-fluorophenoxy)-7-quinolyl)oxy)methyl)-1-piperidinecarboxylate,the mixture was stirred at room temperature for 7 minutes. Saturatedsodium bicarnobate water and ethyl acetate were added to the reactionsolution for extraction. The ethyl acetate layer was washed with brineand dried over sodium sulfate. The drying agent was filtered off and thesolvent was distilled off under reduced pressure to obtain 320 mg of alight yellow solid.

¹H-NMR (DMSO-d₆) δ (ppm): 0.37-0.44 (2H, m), 0.59-0.69 (2H, m),1.47-1.59 (2H, m), 1.92-2.02 (2H, m), 2.14-2.25 (1H, m), 2.47-2.57 (3H,m), 2.87-2.98 (2H, m), 4.19 (2H, d, J=6.4 Hz), 6.59 (1H, d, J=5.2 Hz),6.88 (1H, d, J=2.8 Hz), 7.05-7.10 (1H, m), 7.31 (1H, dd, J=12.0 Hz, 2.8Hz), 7.63 (1H, s), 8.11 (1H, dd, J=9.2 Hz, 9.2 Hz), 8.28 (1H, s), 8.73(1H, d, J=5.2 Hz), 8.74 (1H, s).

Example 6714-(4-(3-Ethylureido)-3-fluorophenoxy)-7-methoxyquinoline-6-carboxylicacid methyl ester

PhenylN-(2-fluoro-4-(7-methoxy-6-methoxycarbonyl-4-quinolyl)oxyphenyl)carbamate(0.9 g) was treated with ethylamine in dimethylsulfoxide at roomtemperature in the same manner as Example 11, to obtain the titlecompound (0.6 g) as a solid.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.05 (3H, t, J=7.2 Hz), 3.07-3.15(2H, m), 3.85 (3H, s), 3.96 (3H, s), 6.52 (1H, d, J=5.2 Hz), 6.58 (1H,t, J=5.2 Hz), 7.04-7.08 (1H, m), 7.31 (1H, dd, J=2.8 Hz, J=12 Hz), 7.51(1H, s), 8.21 (1H, t, J=9.2 Hz), 8.33 (1H, br s), 8.55 (1H, s), 8.67(1H, d, J=5.2 Hz).

The intermediates were synthesized in the following manner.

Production Example 671-1 Methyl4-(4-nitro-3-fluorophenoxy)-7-methoxy-6-quinolinecarboxylate

Methyl 4-(4-nitro-3-fluorophenoxy)-7-methoxy-6-quinolinecarboxylate(2.44 g) was obtained from 4-chloro-7-methoxy-6-methoxycarbonylquinoline(2.51 g), by the same procedure as in Production Example 7.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.83 (3H, s), 3.99 (3H, s), 6.93 (1H,d, J=5.1 Hz), 7.30-7.33 (1H, m), 7.58 (1H, m), 7.65-7.69 (1H, m),8.27-831 (1H, m), 8.44 (1H, s), 8.81 (1H, d, J=5.1 Hz).

Production Example 671-2 Methyl4-(4-amino-3-fluorophenoxy)-7-methoxy-6-quinolinecarboxylate

Methyl 4-(4-amino-3-fluorophenoxy)-7-methoxy-6-quinolinecarboxylate(1.54 g) was obtained from methyl4-(4-nitro-3-fluorophenoxy)-7-methoxy-6-quinolinecarboxylate (2.40 g),by the same procedure as in Production Example 8.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.84 (3H, s), 3.95 (3H, s), 5.21 (2H,brd), 6.46 (1H, d, J=5.1 Hz), 6.85-6.86 (2H, m), 7.09 (1H, d, J=11.9Hz), 7.49 (1H, s), 8.55 (1H, s), 8.65 (1H, d, J=5.1 Hz).

Production Example 671-3 PhenylN-(2-fluoro-4-(7-methoxy-6-methoxycarbonyl-4-quinolyl)oxyphenyl)carbamate

PhenylN-(2-fluoro-4-(7-methoxy-6-methoxycarbonyl-4-quinolyl)oxyphenyl)carbamate(1.87 g) was obtained from methyl4-(4-amino-3-fluorophenoxy)-7-methoxy-6-quinolinecarboxylate (1.50 g),by the same procedure as in Production Example 17.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 3.98 (3H, s), 4.05 (3H, s), 6.49 (1H,d, J=5.3 Hz), 7.03-7.05 (2H, m), 7.22-7.28 (4H, m), 7.50 (1H, s), 8.25(1H, brs), 8.67 (1H, d, J=5.1 Hz), 8.77 (1H, s).

Example 6724-(4-(3-Cyclopropylureido)-3-fluorophenoxy)-7-methoxyquinoline-6-carboxylicacid methyl ester

PhenylN-(2-fluoro-4-(7-methoxy-6-methoxycarbonyl-4-quinolyl)oxyphenyl)carbamate(0.9 g) was treated with cyclopropylamine in dimethylsulfoxide at roomtemperature in the same manner as Example 11, to obtain the titlecompound (0.5 g) as a solid.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.37-0.41 (2H, m), 0.60-0.66 (2H, m),2.51-2.57 (1H, m), 3.47 (3H, s), 3.59 (3H, s), 6.52 (1H, d, J=5.6 Hz),6.79-6.82 (1H, m), 7.05-7.10 (1H, m), 7.32 (1H, dd, J=2.8 Hz, J=11.6Hz), 7.51 (1H, s), 8.17-8.24 (2H, m), 8.55 (1H, s), 8.30 (1H, d, J=5.6Hz).

Example 6734-(4-(3-Ethylureido)-3-fluorophenoxy)-7-methoxyquinoline-6-carboxylicacid

4-(4-(3-Ethylureido)-3-fluorophenoxy)-7-methoxyquinoline-6-carboxylicacid methyl ester (600 mg) was hydrolyzed in the same manner as Example633, to obtain the title compound (210 mg) as a solid.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.05 (3H, t, J=7.2 Hz), 3.07-3.15(2H, m), 3.96 (3H, s), 6.54 (1H, d, J=5.2 Hz), 6.77 (1H, t, J=5.6 Hz),7.03-7.09 (1H, m), 7.31 (1H, dd, J=2.4 Hz, J=11.6 Hz), 7.50 (1H, s),8.21 (1H, t, J=9.2 Hz), 8.45 (1H, br s), 8.56 (1H, s), 8.67 (1H, d,J=5.2 Hz).

Example 6744-(4-(3-Cyclopropylureido)-3-fluorophenoxy)-7-methoxyquinoline-6-carboxylicacid

4-(4-(3-Cyclopropylureido)-3-fluorophenoxy)-7-methoxy-quinoline-6-carboxylicacid methyl ester (500 mg) was hydrolyzed in the same manner as Example633, to obtain the title compound (220 mg) as a solid.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.38-0.43 (2H, m), 0.61-0.67 (2H, m),2.51-2.58 (1H, m), 3.95 (3H, s), 6.52 (1H, d, J=5.2 Hz), 6.83 (1H, d,J=2.8 Hz), 7.05-7.09 (1H, m), 7.31 (1H, dd, J=2.4 Hz, J=11.6 Hz), 7.47(1H, s), 8.20 (1H, t, J=9.2 Hz), 8.22-8.26 (1H, m), 8.46 (1H, s), 8.65(1H, d, J=5.2 Hz).

Example 6754-(4-(3-Ethylureido)-3-fluorophenoxy)-7-methoxyquinoline-6-carboxylicacid methoxyamide

4-(4-(3-Ethylureido)-3-fluorophenoxy)-7-methoxyquinoline-6-carboxylicacid (65 mg) was treated with methoxylamine, triethylamine andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphatein the same manner as Example 634, to obtain the title compound (21 mg)as a solid.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.05 (3H, t, J=7.2 Hz), 3.08-3.15(2H, m), 3.73 (3H, s), 3.97 (3H, s), 6.52 (1H, d, J=5.2 Hz), 6.56-6.61(1H, m), 7.02-7.07 (1H, m), 7.30 (1H, dd, J=2.4 Hz, J=11.6 Hz), 7.48(1H, s), 8.22 (1H, t, J=9.2 Hz), 8.33 (1H, br s), 8.41 (1H, s), 8.65(1H, d, J=5.2 Hz), 11.44 (1H, br s).

Example 6764-(4-(3-Ethylureido)-3-fluorophenoxy)-7-methoxyquinoline-6-carboxylicacid cis-(2-fluorocyclopropyl)amide

4-(4-(3-Ethylureido)-3-fluorophenoxy)-7-methoxyquinoline-6-carboxylicacid (20 mg) was treated with cis-2-fluorocyclopropylamine,triethylamine and benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate in the same manner as Example 634, to obtain thetitle compound (9 mg) as a solid.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.05 (3H, t, J=7.2 Hz), 1.04-1.18(2H, m), 2.87-2.95 (1H, m), 3.08-3.15 (2H, m), 3.99 (3H, s), 4.69-4.74(0.5H, m), 4.86-4.90 (0.5H, m), 6.52 (1H, d, J=5.2 Hz), 6.58 (1H, t,J=5.2 Hz), 7.02-7.07 (1H, m), 7.30 (1H, dd, J=2.4 Hz, J=11.6 Hz), 7.51(1H, s), 8.21 (1H, t, J=9.2 Hz), 8.31-8.35 (1H, m), 8.45 (1H, d, J=4Hz), 8.50 (1H, s), 8.65 (1H, d, J=5.2 Hz).

Example 6774-(4-(3-Ethylureido)-3-fluorophenoxy)-7-methoxyquinoline-6-carboxylicacid (2-ethoxyethyl)-amide

4-(4-(3-Ethylureido)-3-fluorophenoxy)-7-methoxyquinoline-6-carboxylicacid (50 mg) was treated with ethoxyethylamine, triethylamine andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphatein the same manner as Example 634, to obtain the title compound (18 mg)as a solid.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.05 (3H, t, J=7.2 Hz), 1.13 (3H, t,J=7.2 Hz), 3.07-3.15 (2H, m), 3.46-3.57 (6H, m), 4.02 (3H, s), 6.52 (1H,d, J=5.2 Hz), 6.58 (1H, t, J=5.2 Hz), 7.02-7.07 (1H, m), 7.30 (1H, dd,J=2.4 Hz, J=11.6 Hz), 7.51 (1H, s), 8.21 (1H, t, J=9.2 Hz), 8.31-8.35(1H, m), 8.44 (1H, t, J=5.2 Hz), 8.61 (1H, s), 8.65 (1H, d, J=5.2 Hz).

Example 6784-(4-(3-Ethylureido)-3-fluoro-phenoxy)-7-methoxyquinoline-6-carboxylicacid (2-cyanoethyl)amide

4-(4-(3-Ethylureido)-3-fluoro-phenoxy)-7-methoxyquinoline-6-carboxylicacid (40 mg) was treated with cyanoethylamine, triethylamine andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphatein the same manner as Example 634, to obtain the title compound (29 mg)as a solid.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.05 (3H, t, J=7.2 Hz), 2.78 (2H, t,J=6.4 Hz), 3.07-3.15 (2H, m), 3.52-3.58 (2H, m), 4.01 (3H, s), 6.52 (1H,d, J=5.2 Hz), 6.56-6.61 (1H, m), 7.02-7.07 (1H, m), 7.30 (1H, dd, J=2.4Hz, J=11.6 Hz), 7.52 (1H, s), 8.21 (1H, t, J=9.2 Hz), 8.33 (1H, br s),8.59 (1H, s), 8.65 (1H, d, J=5.2 Hz), 8.72 (1H, t, J=6 Hz).

Example 6791-(4-(7-Benzyloxy-6-cyanoquinolin-4-yloxy)-2-methylphenyl)-3-ethylurea

A carbamate (2.1 g) was obtained as a solid from4-(4-amino-3-methylphenoxy)-7-benzyloxyquinoline-6-carbonitrile (2 g)and phenyl chlorocarbonate, in the same manner as Production Example 17.The carbamate (1 g) was then treated with ethylamine indimethylsulfoxide at room temperature in the same manner as Example 11,to obtain the title compound (0.87 g) as a solid.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.57 (3H, t, J=7.2 Hz), 2.20 (3H, s),3.07-3.15 (2H, m), 5.43 (2H, s), 6.48-6.55 (2H, m), 7.02 (1H, dd, J=2.8Hz, J=8.8 Hz), 7.08 (1H, d, J=2.8 Hz), 7.34-7.55 (5H, m), 7.68 (2H, s),7.92 (1H, d, J=8.8 Hz), 8.70 (1H, d, J=5.6 Hz), 8.74 (1H, s).

Example 680N-(4-(6-Cyano-7-hydroxyquinolin-4-yloxy)-2-methylphenyl)-N′-ethylurea

In the same manner as Production Example 301-2,N-(4-(7-benzyloxy-6-cyanoquinolin-4-yloxy)-2-methylphenyl)-N′-ethylurea(0.8 g) was debenzylated in tetrahydrofuran using palladium-carbon, toobtain the title compound (0.42 g) as a solid.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.06 (3H, t, J=7.2 Hz), 2.20 (3H, s),3.07-3.15 (2H, m), 6.37 (1H, d, J=5.2 Hz), 6.52 (1H, t, J=5.6 Hz), 7.01(1H, dd, J=2.8 Hz, J=8.8 Hz), 7.08 (1H, d, J=2.8 Hz), 7.35 (1H, s), 7.68(1H, s), 7.93 (1H, d, J=8.8 Hz), 8.59 (1H, d, J=5.2 Hz), 8.61 (1H, s).

Example 681N-(4-(6-Cyano-7-(piperidin-4-ylmethoxy)quinolin-4-yloxy)-2-methylphenyl)-N′-cyclopropylurea

The target substance was obtained fromN-(4-(6-cyano-7-hydroxyquinolin-4-yloxy)-2-methylphenyl)-N′-cyclopropylurea(410 mg) and 4-bromoethyl-piperidine-1-carboxylic acid tert-butyl ester,in the same manner as Example 7, and was deprotected to obtain the titlecompound (15 mg) as a solid.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.37-0.43 (2H, m), 0.63-0.66 (2H, m),1.44-1.56 (2H, m), 1.92-1.98 (2H, m), 2.11-2.20 (1H, m), 2.20 (3H, s),2.51-2.58 (1H, m), 2.85-2.94 (2H, m), 3.15-3.45 (2H, m), 4.19 (2H, d,J=6.4 Hz), 6.51 (1H, d, J=5.2 Hz), 6.79 (1H, d, J=2.8 Hz), 7.04 (1H, dd,J=2.8 Hz, J=8.8 Hz), 7.10 (1H, d, J=2.8 Hz), 7.62 (1H, s), 7.64 (1H, s),7.93 (1H, d, J=8.8 Hz), 8.71 (1H, d, J=5.2 Hz), 8.75 (1H, s).

Example 682N-(4-(6-Cyano-7-(1-methyl-piperidin-4-ylmethoxy)quinolin-4-yloxy)-2-methylphenyl)-N′-cyclopropylurea

The title compound (3 mg) was obtained as a solid fromN-(4-(6-cyano-7-(piperidin-4-ylmethoxy)quinolin-4-yloxy)-2-methylphenyl)-N′-cyclopropylurea(10 mg), in the same manner as Example 670.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.38-0.44 (2H, m), 0.61-0.67 (2H, m),1.38-1.50 (2H, m), 1.78-1.85 (2H, m), 2.04-2.13 (1H, m), 2.20 (3H, s),2.26 (3H, br s), 2.48-2.58 (1H, m), 2.84-2.99 (2H, m), 3.04-3.54 (2H,m), 4.15 (2H, d, J=6 Hz), 6.50 (1H, d, J=5.2 Hz), 6.82 (1H, d, J=2.8Hz), 7.04 (1H, dd, J=2.4 Hz, J=8.8 Hz), 7.10 (1H, d, J=2.4 Hz), 7.58(1H, s), 7.66 (1H, s), 7.93 (1H, d, J=8.8 Hz), 8.71 (1H, d, J=5.2 Hz),8.73 (1H, s).

Example 683N-(4-(6-Cyano-7-(piperidin-4-ylmethoxy)quinolin-4-yloxy)-2-methylphenyl)-N′-ethylurea

The target substance was obtained fromN-(4-(6-cyano-7-hydroxyquinolin-4-yloxy)-2-methylphenyl)-N′-ethylurea(410 mg) and 4-bromoethyl-piperidine-1-carboxylic acid tert-butyl ester,in the same manner as Example 7, and was deprotected to obtain the titlecompound (15 mg) as a solid.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.06 (3H, t, J=7.2 Hz), 1.44-1.57(2H, m), 1.93-1.99 (2H, m), 2.11-2.20 (1H, m), 2.20 (3H, s), 2.88-2.98(2H, m), 3.07-3.14 (2H, m), 3.15-3.45 (2H, m), 4.19 (2H, d, J=6 Hz),6.51 (1H, d, J=5.2 Hz), 6.57 (1H, t, J=5.6 Hz), 7.02 (1H, dd, J=2.4 Hz,J=8.8 Hz), 7.09 (1H, d, J=2.4 Hz), 7.62 (1H, s), 7.73 (1H, s), 7.94 (1H,d, J=8.8 Hz), 8.71 (1H, d, J=5.2 Hz), 8.74 (1H, s).

Example 684N-(4-(6-Cyano-7-(1-methyl-piperidin-4-ylmethoxy)quinolin-4-yloxy)-2-methylphenyl)-N′-ethylurea

The title compound (5 mg) was obtained as a solid fromN-(4-(6-cyano-7-(piperidin-4-ylmethoxy)quinolin-4-yloxy)-2-methylphenyl)-N′-ethylurea(15 mg), in the same manner as Example 670.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.06 (3H, t, J=7.2 Hz), 1.38-1.51(2H, m), 1.78-1.86 (2H, m), 2.07-2.18 (1H, m), 2.20 (3H, s), 2.28 (3H,br s), 2.89-2.97 (2H, m), 3.07-3.15 (2H, m), 3.15-3.41 (2H, m), 4.15(2H, d, J=6 Hz), 6.50 (1H, d, J=5.2 Hz), 6.58 (1H, t, J=5.6 Hz), 7.03(1H, dd, J=2.8 Hz, J=8.8 Hz), 7.09 (1H, d, J=2.4 Hz), 7.58 (1H, s), 7.73(1H, s), 7.94 (1H, d, J=8.8 Hz), 8.79 (1H, d, J=5.2 Hz), 8.73 (1H, s).

Example 697 Methyl4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylate

PhenylN-(2-chloro-4-(7-methoxy-6-methoxycarbonyl-4-quinolyl)oxyphenyl)carbamate(1.92 g, 4.00 mmol) and 2 M ethylamine (tetrahydrofuran solution) (4 ml)were stirred in dimethylformamide (8 ml) at room temperature for 30minutes. The reaction solution was distributed between ethyl acetate andwater, the organic layer was washed with water and saturated brine anddried over anhydrous magnesium sulfate, and the drying agent wasfiltered out and the filtrate distilled off under reduced pressure. Theobtained crude product was suspended in ethyl acetate, the suspensionwas diluted with hexane, and the crystals were filtered out, washed withhexane and blow-dried to obtain the title compound (1.60 g, 3.72 mmol,93%) as white crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.09 (3H, t, J=7.4 Hz), 3.15 (2H, m),3.87 (3H, s), 3.99 (3H, s), 6.54 (1H, d, J=5.2 Hz), 7.01 (1H, t, J=5.4Hz), 7.25 (1H, dd, J=2.8, 9.0 Hz), 7.50 (1H, d, J=2.8 Hz), 7.54 (1H, s),8.08 (1H, s), 8.28 (1H, d, J=9.0 Hz), 8.58 (1H, s), 8.69 (1H, d, J=5.2Hz).

Example 6984-(3-Chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid

After adding methanol (14 ml) and 2N sodium hydroxide aqueous solution(7 ml) to methyl4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylate(1.50 g, 3.49 mmol), the mixture was stirred at 60° C. for 90 minutes.The reaction solution was allowed to cool to room temperature, and afterneutralization by addition of 2N hydrochloric acid, the methanol wasdistilled off and the precipitated white crystals were filtered out,thoroughly washed with water and dried at 60° C. to obtain the titlecompound (1.36 g, 3.27 mmol, 94%).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.09 (3H, t, J=7.4 Hz), 3.15 (2H, m),3.98 (3H, s), 6.53 (1H, d, J=5.0 Hz), 7.00 (1H, t, J=5.4 Hz), 7.25 (1H,dd, J=2.8, 9.0 Hz), 7.48-7.53 (2H, m), 8.08 (1H, s), 8.27 (1H, d, J=9.0Hz), 8.54 (1H, s), 8.68 (1H, d, J=5.0 Hz), 13.12 (1H, brs).

Example 699N6-Methyl-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

After dissolving4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid (104 mg, 0.250 mmol) in dimethylformamide (3 ml), there were addeda 40% methylamine-methanol solution (0.100 ml), triethylamine (0.250 ml)and1H-1,2,3-benzotriazol-1-yloxy)(tri(dimethylamino))phosphoniumhexafluorophosphate(221 mg, 0.500 mmol) in that order at room temperature, and the mixturewas stirred for 15 hours. The reaction solution was distributed betweenethyl acetate and water, and the organic layer was washed with water andsaturated brine and dried over anhydrous magnesium sulfate. Afterdistilling off the solvent, the residue was suspended in ethyl acetate,the suspension was diluted with hexane and the crystals were filteredout and blow-dried to obtain the title compound (79.0 mg, 0.184 mmol,74%) as white crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.08 (3H, t, J=7.4 Hz), 2.85 (3H, d,J=4.2 Hz), 3.15 (2H, m), 4.02 (3H, s), 6.53 (1H, d, J=5.2 Hz), 7.00 (1H,t, J=5.2 Hz), 7.22 (1H, dd, J=2.8, 9.2 Hz), 7.47 (1H, d, J=2.8 Hz), 7.52(1H, s), 8.07 (1H, s), 8.26 (1H, d, J=9.2 Hz), 8.36 (1H, q, J=4.2 Hz),8.59 (1H, s), 8.67 (1H, d, J=5.2 Hz).

Example 700N6-Ethyl-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (90.0 mg, 0.203 mmol, 81%) was obtained as whitecrystals from4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid (104 mg, 0.250 mmol) and 2.0 M ethylamine (tetrahydrofuransolution), by the same procedure as in Example 699.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.09 (3H, t, J=7.4 Hz), 1.15 (3H, t,J=7.2 Hz), 3.15 (2H, m), 3.28-3.38 (2H, m), 4.02 (3H, s), 6.53 (1H, d,J=5.2 Hz), 7.00 (1H, t, J=5.4 Hz), 7.22 (1H, dd, J=2.8, 9.2 Hz), 7.47(1H, d, J=2.8 Hz), 7.51 (1H, s), 8.07 (1H, s), 8.27 (1H, d, J=9.2 Hz),8.40 (1H, t, J=5.4 Hz), 8.54 (1H, s), 8.66 (1H, d, J=5.2 Hz).

Example 701N6-Cyclopropyl-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (83.0 mg, 0.182 mmol, 73%) was obtained as whitecrystals from4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid (104 mg, 0.250 mmol) and cyclopropylamine, by the same procedure asin Example 699.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.58 (2H, m), 0.71 (2H, m), 1.08 (3H,t, J=7.4 Hz), 2.87 (1H, m), 3.14 (2H, m), 3.99 (3H, s), 6.53 (1H, d,J=5.2 Hz), 7.00 (1H, t, J=4.8 Hz), 7.21 (1H, dd, J=2.8, 9.2 Hz), 7.47(1H, d, J=2.8 Hz), 7.49 (1H, s), 8.07 (1H, s), 8.27 (1H, d, J=9.2 Hz),8.34 (1H, d, J=4.0 Hz), 8.42 (1H, s), 8.66 (1H, d, J=5.2 Hz).

Example 702N6-Methoxy-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (52.0 mg, 0.117 mmol, 47%) was obtained as whitecrystals from4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid (104 mg, 0.250 mmol) and methoxylamine hydrochloride, by the sameprocedure as in Example 699.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.09 (3H, t, J=7.4 Hz), 3.15 (2H, m),3.75 (3H, s), 4.00 (3H, s), 6.54 (1H, d, J=5.2 Hz), 7.00 (1H, t, J=5.4Hz), 7.23 (1H, dd, J=2.8, 9.2 Hz), 7.48 (1H, d, J=2.8 Hz), 7.50 (1H, s),8.07 (1H, s), 8.27 (1H, d, J=9.2 Hz), 8.43 (1H, s), 8.67 (1H, d, J=5.2Hz), 11.45 (1H, s).

Example 703N6-(2-Methoxyethyl)-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (71.0 mg, 0.150 mmol, 60%) was obtained as whitecrystals from4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid (104 mg, 0.250 mmol) and 2-methoxyethylamine, by the same procedureas in Example 699.

¹H-NMR Spectrum (DMSO-d₆) d (ppm): 1.08 (3H, t, J=7.4 Hz), 3.15 (2H, m),3.30 (3H, s), 3.47-3.52 (4H, m), 4.03 (3H, s), 6.54 (1H, d, J=5.2 Hz),7.00 (1H, t, J=5.4 Hz), 7.23 (1H, dd, J=2.8, 9.2 Hz), 7.48 (1H, d, J=2.8Hz), 7.53 (1H, s), 8.07 (1H, s), 8.27 (1H, d, J=9.2 Hz), 8.44 (1H, m),8.62 (1H, s), 8.67 (1H, d, J=5.2 Hz).

Example 704N6-(2-Fluoroethyl)-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (80.0 mg, 0.174 mmol, 69%) was obtained as whitecrystals from4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid (104 mg, 0.250 mmol) and 2-fluoroethylamine hydrochloride, by thesame procedure as in Example 699.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.08 (3H, t, J=7.4 Hz), 3.15 (2H, m),3.59 (1H, m), 3.67 (1H, m), 4.03 (3H, s), 4.51 (1H, m), 4.63 (1H, m),6.54 (1H, d, J=5.2 Hz), 7.00 (1H, t, J=5.4 Hz), 7.23 (1H, dd, J=2.8, 9.2Hz), 7.48 (1H, d, J=2.8 Hz), 7.53 (1H, s), 8.07 (1H, s), 8.27 (1H, d,J=9.2 Hz), 8.58-8.62 (2H, m), 8.67 (1H, d, J=5.2 Hz).

Example 705N6-((2R)Tetrahydro-2-furanylmethyl)-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (99.0 mg, 0.198 mmol, 79%) was obtained as a whitepowder from4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid (104 mg, 0.250 mmol) and R-tetrahydrofurfurylamine, by the sameprocedure as in Example 699.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.08 (3H, t, J=7.4 Hz), 1.62 (1H, m),1.80-2.00 (3H, m), 3.15 (2H, m), 3.40 (2H, m), 3.66 (1H, dd, J=3.6, 14.0Hz), 3.81 (1H, dd, J=4.0, 14.0 Hz), 3.99 (1H, m), 4.04 (3H, s), 6.54(1H, d, J=5.2 Hz), 7.00 (1H, t, J=5.4 Hz), 7.23 (1H, dd, J=2.8, 8.8 Hz),7.48 (1H, d, J=2.8 Hz), 7.54 (1H, s), 8.07 (1H, s), 8.26 (1H, d, J=8.8Hz), 8.43 (1H, t, J=5.6 Hz), 8.61 (1H, s), 8.67 (1H, d, J=5.2 Hz).

Example 706N6-((2S)Tetrahydro-2-furanylmethyl)-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (87.0 mg, 0.174 mmol, 70%) was obtained as a whitepowder from4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid (104 mg, 0.250 mmol) and S-tetrahydrofurfurylamine, by the sameprocedure as in Example 699.

Example 707N6-(2-Ethoxyethyl)-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (112 mg, 0.239 mmol, 95%) was obtained as a whitepowder from4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid (104 mg, 0.250 mmol) and 2-ethoxyethylamine, by the same procedureas in Example 699.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.08 (3H, t, J=7.4 Hz), 1.16 (3H, t,J=6.8 Hz), 3.15 (2H, m), 3.45-3.56 (6H, m), 4.03 (3H, s), 6.54 (1H, d,J=5.2 Hz), 7.01 (1H, m), 7.23 (1H, dd, J=2.8, 9.2 Hz), 7.48 (1H, d,J=2.8 Hz), 7.54 (1H, s), 8.08 (1H, s), 8.27 (1H, dd, J=2.8, 9.2 Hz),8.46 (1H, m), 8.64 (1H, d, J=2.0 Hz), 8.68 (1H, d, J=5.2 Hz).

Example 708N6-Isobutoxy-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (64.0 mg, 0.131 mmol, 53%) was obtained as a whitepowder from4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylicacid (104 mg, 0.250 mmol) and isobutoxylamine hydrochloride, by the sameprocedure as in Example 699.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.95 (6H, d, J=6.8 Hz), 1.08 (3H, t,J=7.4 Hz), 1.97 (1H, m), 3.15 (2H, m), 3.71 (2H, d, J=6.8 Hz), 3.99 (3H,s), 6.54 (1H, d, J=5.2 Hz), 7.00 (1H, m), 7.23 (1H, dd, J=2.8, 9.2 Hz),7.47 (1H, d, J=2.8 Hz), 7.50 (1H, s), 8.08 (1H, s), 8.27 (1H, dd, J=2.8,9.2 Hz), 8.36 (1H, s), 8.67 (1H, d, J=5.2 Hz), 11.36 (1H, br s).

Example 709N6-Ethyl-4-(3-chloro-4-(((methylamino)carbonyl)amino)phenoxy)-7-((2R)-3-diethylamino-2-hydroxypropoxy)-6-quinolinecarboxamide

After adding (2R)oxiran-2-ylmethyl 4-methyl-1-benzenesulfonate (66 mg,0.290 mmol), potassium carbonate (32 mg, 0.231 mmol) anddimethylformamide (2 ml) toN6-ethyl-4-(3-chloro-4-(((methylamino)carbonyl)amino)phenoxy)-7-hydroxy-6-quinolinecarboxamide(80.0 mg, 0.193 mmol), the mixture was stirred at 60° C. for 7 hours.Diethylamine (1 ml) was then added, and the mixture was stirred at 60°C. overnight. The reaction solution was distributed between ethylacetate-tetrahydrofuran (1:1) and water, and the organic layer waswashed with water and saturated brine and then dried over anhydroussodium sulfate. The solvent was distilled off, the residue was subjectedto silica gel column chromatography (eluent-ethylacetate:methanol=95:5), the fraction containing the target substance wasconcentrated, and crystals were precipitated from ethyl acetate-hexane(1:1), filtered out and blow-dried to obtain the title compound (51.7mg, 0.095 mmol, 49.3%) as white crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.94 (6H, t, J=7.2 Hz), 1.16 (3H, t,J=7.2 Hz), 2.40-2.60 (6H, m), 2.66 (3H, d, J=4.8 Hz), 3.20-3.40 (2H, m),3.98 (1H, m), 4.19 (1H, dd, J=5.2, 10.0 Hz), 4.31 (1H, dd, J=3.2, 10.0Hz), 5.09 (1H, d, J=4.8 Hz), 6.51 (1H, d, J=5.2 Hz), 6.86 (1H, q, J=4.8Hz), 7.22 (1H, dd, J=2.8, 9.2 Hz), 7.47 (1H, d, J=2.8 Hz), 7.52 (1H, s),8.10 (1H, s), 8.23 (1H, d, J=9.2 Hz), 8.54 (1H, m), 8.65 (1H, d, J=5.2Hz), 8.73 (1H, s).

Example 710N6-Ethyl-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-((2R)-3-diethylamino-2-hydroxypropoxy)-6-quinolinecarboxamide

The title compound (44.5 mg, 0.080 mmol, 43.8%) was obtained as whitecrystals fromN6-ethyl-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-hydroxy-6-quinolinecarboxamide(78.0 mg, 0.182 mmol), by the same procedure as in Example 709.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.94 (6H, t, J=7.2 Hz), 1.06 (3H, t,J=7.2 Hz), 1.16 (3H, t, J=7.2 Hz), 2.40-2.60 (6H, m), 3.12 (2H, m),3.20-3.40 (2H, m), 3.98 (1H, m), 4.22 (1H, dd, J=5.6, 9.6 Hz), 4.31 (1H,dd, J=3.2, 9.6 Hz), 5.08 (1H, d, J=4.4 Hz), 6.51 (1H, d, J=5.2 Hz), 6.98(1H, m), 7.22 (1H, dd, J=2.8, 9.2 Hz), 7.47 (1H, d, J=2.8 Hz), 7.52 (1H,s), 8.05 (1H, s), 8.25 (1H, d, J=9.2 Hz), 8.54 (1H, m), 8.65 (1H, d,J=5.2 Hz), 8.73 (1H, s).

Example 711N6-Ethyl-4-(3-chloro-4-(((methylamino)carbonyl)amino)phenoxy)-7-((2R)-2-hydroxy-3-(1-pyrrolidino)propoxy)-6-quinolinecarboxamide

After adding (2R)oxiran-2-ylmethyl 4-methyl-1-benzenesulfonate (66 mg,0.290 mmol), potassium carbonate (32 mg, 0.231 mmol) anddimethylformamide (2 ml) toN6-ethyl-4-(3-chloro-4-(((methylamino)carbonyl)amino)phenoxy)-7-hydroxy-6-quinolinecarboxamide(80.0 mg, 0.193 mmol), the mixture was stirred at 60° C. for 7 hours.After allowing the reaction solution to cool to room temperature,pyrrolidine (0.5 ml) was added and the mixture was further stirredovernight. The reaction solution was distributed between ethylacetate-tetrahydrofuran (1:1) and water, and the organic layer waswashed with water and saturated brine and then dried over anhydroussodium sulfate. The solvent was distilled off, the residue was subjectedto silica gel column chromatography (eluent-ethylacetate:methanol=95:5), the fraction containing the target substance wasconcentrated, and crystals were precipitated from ethyl acetate-hexane(1:1), filtered out and blow-dried to obtain the title compound (54.8mg, 0.101 mmol, 52.4%) as white crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.16 (3H, t, J=7.2 Hz), 1.67 (4H, m),2.40-2.60 (5H, m), 2.65-2.71 (4H, m), 3.20-3.40 (2H, m), 4.05 (1H, m),4.19 (1H, dd, J=6.0, 10.0 Hz), 4.32 (1H, dd, J=3.6, 10.0 Hz), 5.18 (1H,d, J=4.4 Hz), 6.52 (1H, d, J=4.0 Hz), 6.86 (1H, q, J=4.8 Hz), 7.22 (1H,d, J=9.2 Hz), 7.47 (1H, s), 7.52 (1H, s), 8.10 (1H, s), 8.23 (1H, d,J=9.2 Hz), 8.53 (1H, m), 8.65 (1H, d, J=4.0 Hz), 8.71 (1H, s).

Example 712N6-Ethyl-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-((2R)-2-hydroxy-3-(1-pyrrolidino)propoxy)-6-quinolinecarboxamide

The title compound (47.3 mg, 0.085 mmol, 46.8%) was obtained as whitecrystals fromN6-ethyl-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-hydroxy-6-quinolinecarboxamide(78.0 mg, 0.182 mmol), by the same procedure as in Example 711.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.06 (3H, t, J=7.2 Hz), 1.16 (3H, t,J=7.2 Hz), 1.67 (4H, m), 2.40-2.60 (5H, m), 2.68 (1H, dd, J=6.4, 12.0Hz), 3.12 (2H, m), 3.35 (2H, m), 4.05 (1H, m), 4.19 (1H, dd, J=6.4, 10.0Hz), 4.32 (1H, dd, J=3.6, 10.0 Hz), 5.18 (1H, d, J=4.8 Hz), 6.51 (1H, d,J=5.2 Hz), 6.98 (1H, m), 7.21 (1H, dd, J=2.8, 9.2 Hz), 7.47 (1H, d,J=2.8 Hz), 7.52 (1H, s), 8.05 (1H, s), 8.25 (1H, d, J=9.2 Hz), 8.53 (1H,m), 8.65 (1H, d, J=5.2 Hz), 8.71 (1H, s).

Example 713N-(4-((6-Cyano-7-(((2R)-3-(diethylamino)-2-hydroxypropyl)oxy)-4-quinolyl)oxy)phenyl)-N′-(thiazol-2-yl)urea

After dissolving4-(4-aminophenoxy)-6-cyano-7-(((2R)-3-(diethylamino)-2-hydroxypropyl)oxy)quinoline(105 mg, 0.2583 mmol) in dimethylsulfoxide (1 ml), there was addedphenyl(thiazol-2-yl)carbamate (60 mg, 0.2712 mmol), and the mixture washeated and stirred at 85° C. for 40 minutes. After cooling to roomtemperature, water was added to the reaction solution, extraction wasperformed with ethyl acetate-tetrahydrofuran, and the extract was washedwith saturated brine and dried over anhydrous sodium sulfate. Upondistilling off the solvent, the residue was dissolved in acetone anddiluted with diethyl ether, and the precipitate was washed with diethylether and blow-dried to obtain the title compound (75 mg, 0.1408 mmol,54.51%) as a light yellow powder.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.96 (6H, t, J=7.0 Hz), 2.41-2.68(6H, m), 3.96 (1H, m), 4.21 (1H, dd, J=5.2, 10.0 Hz), 4.31 (1H, dd,J=3.2, 10.0 Hz), 4.92 (1H, brs), 6.52 (1H, d, J=5.2 Hz), 7.10 (1H, d,J=3.6 Hz), 7.27 (2H, d, J=9.0 Hz), 7.37 (1H, d, J=3.6 Hz), 7.61 (1H, s),7.63 (2H, d, J=9.0 Hz), 8.72 (1H, d, J=5.2 Hz), 8.76 (1H, s), 9.15 (1H,brs).

The starting materials were synthesized in the following manner.

Production Example 713-1 4-(4-Aminophenoxy)-6-cyano-7-hydroxyquinoline

6-cyano-7-hydroxy-4-(4-nitrophenoxy)quinoline (1.23 g, 4.00 mmol),obtained by deprotecting the benzyl group of the7-benzyloxy-6-cyano-4-(4-nitrophenoxy)quinoline obtained in ProductionExample 5 according to the method of Production Example 21, was used ina reaction for reduction of the nitro group in the same manner asProduction Example 21, to obtain the title compound (0.864 g, 3.1160mmol, 77.90%) as yellowish-brown crystals.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 5.18 (2H, brs), 6.36 (1H, d, J=5.2 Hz),6.65 (2H, d, J=8.4 Hz), 6.92 (2H, d, J=8.4 Hz), 7.38 (1H, s), 8.60 (1H,d, J=5.2 Hz), 8.62 (1H, s).

Production Example 713-24-(4-Aminophenoxy)-6-cyano-7-((2R)-oxiran-2-yl)methoxyquinoline

After dissolving 4-(4-aminophenoxy)-6-cyano-7-hydroxyquinoline (277 mg,1.00 mmol) in dimethylformamide (3.0 ml), sodium hydride (40 mg, 1.00mmol, 60% in oil) was added at room temperature and the mixture wasstirred. There was then added (2R)-oxiran-2-ylmethyl4-methyl-1-benzenesulfonate (228 mg, 1.00 mmol), and the mixture washeated and stirred at 60° C. for 5 hours. After cooling to roomtemperature, the reaction solution was distributed between ethyl acetateand water. The organic layer was washed with saturated brine and driedover anhydrous sodium sulfate, and the solvent was distilled off toobtain the title compound (322 mg, 0.97 mmol, 97%) as a yellow solid.

¹H-NMR Spectrum (DMSO-d6) δ (ppm): 2.82 (1H, dd, J=2.8, 4.8 Hz), 2.93(1H, dd, J=4.8, 4.8 Hz), 3.48 (1H, m), 4.17 (1H, dd, J=6.6, 12.0 Hz),4.71 (1H, dd, J=2.0, 12.0 Hz), 5.20 (2H, m), 6.49 (1H, d, J=5.2 Hz),6.68 (2H, d, J=8.8 Hz), 6.96 (2H, d, J=8.8 Hz), 7.62 (1H, s), 8.71 (1H,d, J=5.2 Hz), 8.76 (1H, s).

Production Example 713-34-(4-Aminophenoxy)-6-cyano-7-(((2R)-3-(diethylamino)-2-hydroxypropyl)oxy)quinoline

The title compound (105 mg, 0.2583 mmol, 29.02%) was obtained as a lightyellow oil using4-(4-aminophenoxy)-6-cyano-7-((2R)-oxiran-2-yl)methoxyquinoline (297 mg,0.8900 mmol), by the same procedure as in Production Example 429-2.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.08 (6H, t, J=7.0 Hz), 1.50-2.50 (1H,brs), 2.55-2.76 (6H, m), 3.79 (2H, brs), 4.15 (1H, m), 4.24 (2H, d,J=4.8 Hz), 6.46 (1H, d, J=5.4 Hz), 6.77 (2H, d, J=8.8 Hz), 6.96 (2H, d,J=8.8 Hz), 7.48 (1H, s), 8.64 (1H, d, J=5.4 Hz), 8.69 (1H, s).

Example 714N-(4-((6-Cyano-7-(((2R)-2-hydroxy-3-(pyrrolidin-1-yl)propyl)oxy)-4-quinolyl)oxy)phenyl)-N′-(thiazol-2-yl)urea

4-(4-Aminophenoxy)-6-cyano-7-((2R)-oxiran-2-yl)methoxyquinoline (322 mg,0.966 mmol) and thiazol-2-ylcarbamic acid phenyl ester (255 mg, 1.26mmol) were heated and stirred in dimethylsulfoxide (2 ml) at 85° C. for4 hours. The reaction solution was distributed between an ethylacetate-tetrahydrofuran mixed solvent and water, the organic layer waswashed with water and saturated brine and then dried over anhydrousmagnesium sulfate, and the drying agent was filtered off and thefiltrate distilled off under reduced pressure. The obtained product andpyrrolidine (343 mg, 4.83 mmol) were stirred in dimethylformamide (3 ml)at room temperature for 15 hours. The reaction solution was distributedbetween ethyl acetate and water, the organic layer was washed with waterand saturated brine and dried over anhydrous magnesium sulfate, thedrying agent was filtered off, and the filtrate was distilled off underreduced pressure. The obtained crude product was subjected to silica gelcolumn chromatography (eluent-ethyl acetate:methanol=15:1), the fractioncontaining the target substance was concentrated and suspended in ethylacetate, the suspension was diluted with hexane, and the crystals werefiltered out, washed with hexane and blow-dried to obtain the titlecompound (45 mg, 0.085 mmol, 9%) as light yellow crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.67 (4H, m), 2.40-2.60 (5H, m), 2.73(1H, dd, J=6.4, 12.4 Hz), 4.03 (1H, m), 4.22 (1H, dd, J=6.0, 10.0 Hz),4.33 (1H, dd, J=3.2, 10.0 Hz), 5.04 (1H, d, J=5.2 Hz), 6.54 (1H, d,J=5.2 Hz), 7.12 (1H, d, J=3.6 Hz), 7.27-7.32 (2H, m), 7.38 (1H, d, J=3.6Hz), 7.62-7.69 (3H, m), 8.74 (1H, d, J=5.2 Hz), 8.77 (1H, s), 9.25 (1H,br s), 10.73 (1H, br s).

Example 7154-{6-Cyano-4-[4-(3-thiazol-2-ylureido)phenoxy]quinolin-7-yloxymethyl}piperidine-1-carboxylicacid tert-butyl ester

4-(4-(4-Aminophenoxy)-6-cyanoquinolin-7-yloxymethyl)-piperidine-1-carboxylicacid tert-butyl ester (225 mg) was heated in dimethylsulfoxide togetherwith thiazol-2-yl-carbamic acid phenyl ester at 80° C. in the samemanner as Example 713 to obtain the title compound (240 mg) as a solid.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.19-1.32 (2H, m), 1.39 (9H, s),1.75-1.84 (2H, m), 2.01-2.11 (1H, m), 2.66-2.87 (2H, m), 3.94-4.04 (2H,m), 4.17 (2H, d, J=5.6 Hz), 6.52 (1H, d, J=5.2 Hz), 7.11 (1H, d, J=3.2Hz), 7.27 (2H, d, J=8.8 Hz), 7.37 (1H, d, J=3.2 Hz), 7.58 (1H, s), 7.62(2H, d, J=8.8 Hz), 8.71 (1H, d, J=5.2 Hz), 8.75 (1H, s), 9.14 (1H, brs).

The intermediate was synthesized in the following manner.

Production Example 715-14-(4-(4-Aminophenoxy)-6-cyanoquinolin-7-yloxymethyl)-piperidine-1-carboxylicacid tert-butyl ester

After treating 4-(4-aminophenoxy)-7-hydroxyquinoline-6-carbonitrile(0.32 g) with sodium hydride in dimethylformamide in the same manner asProduction Example 713-2, it was reacted with4-bromoethylpiperidine-1-carboxylic acid tert-butyl ester to obtain thetitle compound (225 mg) as a solid.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.18-1.32 (2H, m), 1.39 (9H, s),1.75-1.82 (2H, m), 1.98-2.10 (1H, m), 2.62-2.92 (2H, m), 3.94-4.03 (2H,m), 4.15 (2H, d, J=6 Hz), 5.16-5.21 (2H, m), 6.45 (1H, d, J=5.2 Hz),6.65 (2H, d, J=8.8 Hz), 6.93 (2H, d, J=8.8 Hz), 7.55 (1H, s), 8.68 (1H,d, J=5.2 Hz), 8.70 (1H, s).

Example 7161-(4-(6-Cyano-7-(piperidin-4-ylmethoxy)quinolin-4-yloxy)phenyl)-3-(thiazol-2-yl)urea

4-(6-Cyano-4-(4-(3-thiazol-2-yl-ureido)-phenoxy)-quinolin-7-yloxymethyl)-piperidine-1-carboxylicacid tert-butyl-ester (240 mg) was deprotected with trifluoroacetic acidin the same manner as Production Example 670-4 to obtain the titlecompound (220 mg) as a solid.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.46-1.59 (2H, m), 1.87-1.96 (2H, m),2.06-2.18 (1H, m), 2.78-2.89 (2H, m), 3.08-3.38 (2H, m), 4.13 (2H, d,J=6 Hz), 6.43 (1H, d, J=5.2 Hz), 7.07 (1H, d, J=3.2 Hz), 7.20 (2H, d,J=9.2 Hz), 7.36 (1H, d, J=3.2 Hz), 7.57 (1H, s), 7.68 (2H, d, J=9.2 Hz),8.63 (1H, d, J=5.2 Hz), 8.71 (1H, s), 9.82 (1H, br).

Example 7171-(4-(6-Cyano-7-(1-methylpiperidin-4-ylmethoxy)quinolin-4-yloxy)phenyl)-3-(thiazol-2-yl)urea

The title compound (51 mg) was obtained as a solid from1-(4-(6-cyano-7-(piperidin-4-ylmethoxy)quinolin-4-yloxy)phenyl)-3-(thiazol-2-yl)urea(220 mg), in the same manner as Example 670.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.35-1.48 (2H, m), 1.75-1.85 (2H, m),1.89-1.96 (1H, m), 2.18 (3H, brs), 2.79-2.86 (2H, m), 3.18-3.38 (2H, m),4.15 (2H, d, J=5.6 Hz), 6.52 (1H, d, J=5.2 Hz), 7.10 (1H, d, J=3.2 Hz),7.27 (2H, d, J=9.2 Hz), 7.37 (1H, d, J=3.2 Hz), 7.58 (1H, s), 7.63 (2H,d, J=9.2 Hz), 8.72 (1H, d, J=5.2 Hz), 8.76 (1H, s), 9.20 (1H, br).

Example 718N-(4-(6-Carbamoyl-7-methoxy-4-quinolyl)oxy-2-trifluoromethylphenyl)-N′-ethylurea

Ethylamine 2N tetrahydrofuran solution (0.10 ml) was added todimethylsulfoxide (0.5 ml), and then(4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2-trifluoromethylphenyl)carbamicacid phenyl ester (25 mg) was dissolved therein and the mixture wasstirred for 10 minutes. Water and ethyl acetate were added to thereaction solution, and the precipitated crystals were filtered out toobtain the title compound (5.0 mg).

¹H-NMR (DMSO-d₆) δ (ppm) 1.08 (3H, t, J=7.2 Hz), 3.10-3.18 (2H, m), 4.04(3H, s), 6.54 (1H, d, J=5.2 Hz), 7.00-7.07 (1H, m), 7.51-7.63 (3H, m),7.74 (1H, brs), 7.82-7.88 (2H, m), 8.06-8.13 (1H, m), 8.66-8.70 (2H, m)

Example 719N-[4-(6-Carbamoyl-7-methoxy-4-quinolyl)oxy-2-trifluoromethylphenyl]-N′-methylurea

After adding[4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2-trifluoromethylphenyl]carbamicacid phenyl ester (25 mg) to methylamine 2N tetrahydrofuran solution(1.00 ml), the mixture was stirred for 10 minutes. The precipitatedcrystals were filtered out and washed with tetrahydrofuran to obtain thetitle compound (10 mg).

¹H-NMR (DMSO-d₆) δ (ppm) 2.68 (3H, d, J=4.0 Hz), 4.04 (3H, s), 6.54 (1H,d, J=5.6 Hz), 6.87-6.94 (1H, m), 7.51-7.63 (3H, m), 7.75 (1H, brs), 7.86(1H, brs), 7.90 (1H, brs), 8.03-8.09 (1H, m), 8.66-8.70 (2H, m)

Example 720N-(4-(7-Benzyloxy-6-cyano-quinolin-4-yloxy)-2,3-dimethylphenyl)-N′-cyclopropylurea

Cyclopropylamine (1 ml) was added to dimethylformamide (10 ml), and then(4-(7-benzyloxy-6-cyano-quinolin-4-yloxy)-2,3-dimethylphenyl)carbamicacid phenyl ester (1.99 g) was added thereto and the mixture was stirredat room temperature for 10 minutes. Water (30 ml) and ethyl acetate (30ml) were added, and the precipitated crystals were filtered out andwashed with ethyl acetate to obtain the title compound (1660 mg).

¹H-NMR (DMSO-d₆) δ (ppm) 0.40-0.45 (2H, m), 0.62-0.67 (2H, m), 2.03 (3H,s), 2.16 (3H, s), 2.52-2.59 (1H, m), 5.47 (2H, s), 6.33 (1H, d, J=5.2Hz), 6.68-6.74 (1H, m), 7.00 (1H, d, J=8.8 Hz), 7.35-7.49 (3H, m),7.52-7.73 (5H, m), 8.69 (1H, d, J=5.2 Hz), 8.76 (1H, s)

The starting material was synthesized by the following 2 steps.

Production Example 720-14-(4-Amino-2,3-dimethylphenoxy)-7-benzyloxy-6-cyanoquinoline

4-Amino-2,3-xylenol (2.80 g) purchased from Tokyo Chemical Industrieswas dissolved in dimethylsulfoxide (15 ml), and after gradually addingsodium hydride (816 mg) at room temperature, the mixture was stirred for20 minutes. 7-Benzyloxy-4-chloro-6-cyanoquinoline (3.0 g) was added, andthe mixture was heated at 100° C. for 4 hours while stirring. Aftercooling to room temperature, the reaction solution was distributedbetween ethyl acetate and water, and the organic layer was washed withwater, 1N aqueous sodium hydroxide and saturated brine and dried overanhydrous sodium sulfate. The solvent was distilled off, and theobtained crude product was washed with ethyl acetate to obtain the titlecompound (1.72 g) as light brown crystals.

¹H-NMR (DMSO-d₆) δ (ppm) 1.91 (3H, s), 2.01 (3H, s), 4.83-4.90 (2H, m),5.44 (2H, s), 6.30 (1H, d, J=5.2 Hz), 6.60 (1H, d, J=8.4 Hz), 6.73-6.79(1H, m), 7.33-7.47 (3H, m), 7.51-7.58 (2H, m), 7.67 (1H, s), 8.65 (1H,d, J=5.2 Hz), 8.80 (1H, s)

Production Example 720-2[4-(7-Benzyloxy-6-cyanoquinolin-4-yloxy)-2,3-dimethylphenyl]carbamicacid phenyl ester

The title compound (1.99 g) was obtained as light brown crystals from4-(4-amino-2,3-dimethylphenoxy)-7-benzyloxy-6-cyanoquinoline (1.72 g),by the method described in Production Example 141-1.

¹H-NMR(CDCl₃) δ (ppm) 2.02 (3H, s), 2.13 (3H, s), 5.36 (2H, s), 6.32(1H, d, J=5.2 Hz), 6.78 (1H, brs), 7.00 (1H, d, J=8.8 Hz), 7.20-7.80(12H, m), 8.62 (1H, d, J=5.2 Hz), 8.78 (1H, s)

Example 721N-[2,3-Dimethyl-4-(6-cyano-7-hydroxyquinolin-4-yloxy)phenyl]-N′-cyclopropylurea

After addingN-[4-(7-benzyloxy-6-cyanoquinolin-4-yloxy)-2,3-dimethylphenyl]-N′-cyclopropylurea(1600 mg) to tetrahydrofuran (400 ml), palladium-carbon (2000 mg) wasfurther added and the mixture was stirred overnight at room temperatureunder a hydrogen atmosphere. The palladium-carbon was removed byfiltration, washing was performed with dimethylformamide, and thefiltrate was concentrated under reduced pressure to obtain the titlecompound (827 mg).

¹H-NMR (DMSO-d₆) δ (ppm) 0.40-0.46 (2H, m), 0.62-0.67 (2H, m), 2.03 (3H,s), 2.16 (3H, s), 2.54-2.60 (1H, m), 6.20 (1H, d, J=5.2 Hz), 6.68 (1H,d, J=3.2 Hz), 7.00 (1H, d, J=8.8 Hz), 7.39 (1H, brs), 7.65 (1H, d, J=8.8Hz) 7.69 (1H, s), 8.59 (1H, d, J=5.2 Hz), 8.71 (1H, s)

Example 722N-(4-(6-Cyano-7-(3-pyrrolidin-1-ylpropoxy)quinolin-4-yloxy)-2,3-dimethylphenyl)-N′-cyclopropylurea

After adding theN-[2,3-dimethyl-4-(6-cyano-7-hydroxyquinolin-4-yloxy)phenyl]-N′-cyclopropylurea(100 mg) synthesized in Example 721, 1-(3-chloropropyl)pyrrolidinehydrochloride (95 mg) and potassium carbonate (150 mg) todimethylformamide (2 ml), the mixture was heated at 60° C. for 7 hours.Water was added to the reaction solution, extraction was performed withethyl acetate, and then the organic layer was washed with water andsaturated brine in that order and dried over anhydrous sodium sulfate,and the solvent was distilled off under reduced pressure. The obtainedcrude product was washed with ethyl acetate to obtain the title compound(49 mg) as light yellow crystals.

¹H-NMR(CDCl₃) δ (ppm) 0.38-0.44 (2H, m), 0.59-0.66 (2H, m), 1.64-1.71(4H, m), 1.94-2.00 (2H, m), 2.01 (3H, s), 2.14 (3H, s), 2.40-2.60 (7H,m), 4.33 (2H, t, J=6.4 Hz), 6.30 (1H, d, J=5.6 Hz), 6.82 (1H, brs), 6.99(1H, d, J=8.8 Hz), 7.58 (1H, s), 7.64 (1H, d, J=8.8 Hz) 7.69 (1H, brs),8.67 (1H, d, J=5.6 Hz), 8.80 (1H, s).

Example 723N-(4-(6-Cyano-7-((2R)-2-hydroxy-3-pyrrolidin-1-ylpropoxy)quinolin-4-yloxy)-2,3-dimethylphenyl)-N′-cyclopropylurea

After adding tetrahydrofuran (2.0 ml) and pyrrolidine (0.20 ml) toN-(4-(6-cyano-7-((2R)-oxiran-2-yl)methoxy-quinolin-4-yloxy)-2,3-dimethylphenyl)-N′-cyclopropylurea(110 mg), the mixture was heated at 60° C. for 2 hours. After allowingthe reaction solution to cool, the precipitated crystals were filteredout to obtain the title compound (18 mg) as light brown crystals.

¹H-NMR (DMSO-d₆) δ (ppm) 0.40-0.46 (2H, m), 0.62-0.68 (2H, m), 1.65-1.73(4H, m), 2.03 (3H, s), 2.16 (3H, s), 2.45-2.70 (7H, m), 4.00-4.08 (1H,m), 4.22 (1H, dd, J=10.4, 5.6 Hz), 4.32 (1H, dd, J=10.4, 3.6 Hz), 5.04(1H, d, J=4.4 Hz), 6.32 (1H, d, J=5.6 Hz), 6.67-6.72 (1H, m), 7.02 (1H,d, J=8.8 Hz), 7.61-7.72 (3H, m), 8.69 (1H, d, J=5.6 Hz), 8.82 (1H, s).

The starting material was synthesized in the following manner.

Production Example 723-1N-(4-(6-Cyano-7-((2R)-oxiran-2-yl)methoxyquinolin-4-yloxy)-2,3-dimethylphenyl)-N′-cyclopropylurea

Dimethylformamide (4 ml) was added toN-(2,3-dimethyl-4-(6-cyano-7-hydroxy-quinolin-4-yloxy)-phenyl)-N′-cyclopropylurea(476 mg), and then (2R)-(−)-glycidyl p-toluenesulfonate (365 mg) andpotassium carbonate (340 mg) were further added and the mixture washeated at 50° C. for 4 hours. Water was added to the reaction solution,extraction was performed with ethyl acetate, the organic layer waswashed with water and saturated brine in that order and dried overanhydrous sodium sulfate, and the solvent was distilled off underreduced pressure. The obtained crude product was washed with ethylacetate to obtain the title compound (270 mg) as light yellow crystals.

¹H-NMR (DMSO-d₆) δ (ppm) 0.40-0.46 (2H, m), 0.62-0.68 (2H, m), 2.03 (3H,s), 2.16 (3H, s), 2.52-2.60 (1H, m), 2.80-2.96 (2H, m), 3.45-3.52 (1H,m), 4.18 (1H, dd, J=11.6, 6.4 Hz), 4.73 (1H, dd, J=11.6, 2.0 Hz), 6.34(1H, d, J=5.6 Hz), 6.69-6.74 (1H, m), 7.01 (1H, d, J=8.8 Hz), 7.61-7.75(2H, m), 7.95 (1H, brs), 8.70 (1H, d, J=5.6 Hz), 8.85 (1H, s).

Example 724N-(4-(6-Cyano-7-((2R)-2-hydroxy-3-piperidin-1-ylpropoxy)quinolin-4-yloxy)-2,3-dimethylphenyl)-N′-cyclopropylurea

After adding tetrahydrofuran (2.0 ml) and piperidine (0.20 ml) toN-(4-(6-cyano-7-((2R)-oxiran-2-yl)methoxy-quinolin-4-yloxy)-2,3-dimethylphenyl)-N′-cyclopropylurea(80 mg), the mixture was heated at 60° C. for 4 hours. After allowingthe reaction solution to cool, the precipitated crystals were filteredout to obtain the title compound (50 mg) as light brown crystals.

¹H-NMR (DMSO-d₆) δ (ppm) 0.40-0.46 (2H, m), 0.62-0.68 (2H, m), 1.30-1.55(6H, m), 2.03 (3H, s), 2.16 (3H, s), 2.30-2.70 (7H, m), 4.00-4.09 (1H,m), 4.22 (1H, dd, J=10.4, 5.6 Hz), 4.32 (1H, dd, J=10.4, 3.6 Hz), 4.95(1H, d, J=4.0 Hz), 6.32 (1H, d, J=5.6 Hz), 6.71-6.74 (1H, m), 7.02 (1H,d, J=8.8 Hz), 7.62-7.70 (2H, m), 7.73 (1H, brs), 8.69 (1H, d, J=5.6 Hz),8.82 (1H, s).

Example 725N-(4-(6-Cyano-7-(3-diethylamino-(2R)-2-hydroxy-propoxy)quinolin-4-yloxy)-2,3-dimethylphenyl)-N′-cyclopropylurea

After adding tetrahydrofuran (2.0 ml) and diethylamine (0.50 ml) toN-(4-(6-cyano-7-((2R)-oxiran-2-yl)methoxyquinolin-4-yloxy)-2,3-dimethylphenyl)-N′-cyclopropylurea(80 mg), the mixture was heated at 60° C. for 6 hours. The reactionsolution was allowed to cool, and the precipitated crystals werefiltered out to obtain the title compound (32 mg) as light browncrystals.

¹H-NMR (DMSO-d₆) δ (ppm) 0.40-0.46 (2H, m), 0.62-0.69 (2H, m), 0.98 (6H,t, J=7.2 Hz), 2.03 (3H, s), 2.16 (3H, s), 2.40-2.70 (7H, m), 3.90-4.02(1H, m), 4.22 (1H, dd, J=10.4, 5.6 Hz), 4.32 (1H, dd, J=10.4, 3.6 Hz),4.93 (1H, d, J=4.0 Hz), 6.32 (1H, d, J=5.6 Hz), 6.71-6.74 (1H, m), 7.02(1H, d, J=8.8 Hz), 7.61-7.70 (2H, m), 7.72 (1H, brs), 8.69 (1H, d, J=5.6Hz), 8.82 (1H, s).

Example 726N6-Ethyl-7-benzyloxy-4-(3-chloro-(4-((methylamino)carbonyl)amino)phenoxy)-6-quinolinecarboxamide

N6-Ethyl-4-(4-amino-3-chlorophenoxy)-7-benzyloxy-6-quinolinecarboxamide)(870 mg, 1.94 mmol) and pyridine (460 mg, 5.82 mmol) were dissolved indimethylformamide (10 ml), and after adding phenyl chloroformate (456mg, 2.91 mmol) while cooling on ice, the mixture was stirred at roomtemperature for 18 hours. The reaction solution was distributed betweenethyl acetate and water, the organic layer was washed with water andsaturated brine and dried over anhydrous magnesium sulfate, the dryingagent was filtered off, and the filtrate was distilled off under reducedpressure. A portion of the obtained product (460 mg, 0.810 mmol) and a40% methylamine-methanol solution (0.810 ml) were stirred together indimethylformamide (5 ml) at room temperature for 30 minutes. Thereaction solution was distributed between ethyl acetate and water, theorganic layer was washed with water and saturated brine and dried overanhydrous magnesium sulfate, the drying agent was filtered off, and thefiltrate was distilled off under reduced pressure. The obtained crudeproduct was suspended in ethyl acetate and diluted with hexane, and thenthe crystals were filtered out, washed with hexane and blow-dried toobtain the title compound (359 mg, 0.711 mmol, 74%) as white crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.07 (3H, t, J=7.4 Hz), 2.68 (3H, d,J=4.0 Hz), 3.30 (2H, m), 5.41 (2H, s), 6.54 (1H, d, J=5.2 Hz), 6.89 (1H,m), 7.23 (1H, dd, J=2.8, 9.2 Hz), 7.34-7.40 (1H, m), 7.40-7.49 (3H, m),7.55-7.60 (2H, m), 7.61 (1H, s), 8.13 (1H, s), 8.25 (1H, dd, J=3.2, 9.2Hz), 8.36 (1H, t, J=5.2 Hz), 8.51 (1H, s), 8.66 (1H, d, J=5.2 Hz).

The starting materials were synthesized in the following manner.

Production Example 726-1N6-Ethyl-7-benzyloxy-4-chloro-6-quinolinecarboxamide

After adding thionyl chloride (10 ml) and a catalytic amount ofdimethylformamide to phenyl7-benzyloxy-4-oxo-1,4-dihydro-6-quinolinecarboxylate (2.32 g, 6.25mmol), the mixture was heated to reflux for 2 hours while stirring. Thereaction solution was concentrated under reduced pressure andazeotropically distilled twice with toluene, the residue was dissolvedin a dimethylformamide (10 ml) and triethylamine (5 ml) mixed solvent,2M ethylamine (tetrahydrofuran solution) (6.25 ml, 12.5 mmol) wasgradually added thereto while cooling in an ice water bath, and themixture was stirred at room temperature for 3 hours. The reactionsolution was distributed between ethyl acetate and water, and then theorganic layer was washed with ammonia water, water and saturated brineand dried over anhydrous magnesium sulfate. The solvent was distilledoff, after which ethyl acetate and then diethyl ether were added forcrystallization and the crystals were filtered out and blow-dried toobtain the title compound (723 mg, 2.12 mmol, 34%) as yellow crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.08 (3H, t, J=7.2 Hz), 3.30 (2H, m),5.41 (2H, s), 7.34-7.39 (1H, m), 7.40-7.46 (2H, m), 7.54-7.59 (2H, m),7.66 (1H, d, J=4.8 Hz), 7.70 (1H, s), 8.36 (1H, s), 8.42 (1H, m), 8.81(1H, d, J=4.8 Hz).

Production Example 726-2N6-Ethyl-4-(4-amino-3-chlorophenoxy)-7-benzyloxy-6-quinolinecarboxamide

After dissolving 4-amino-3-chlorophenol (379 mg, 2.64 mmol) indimethylsulfoxide (10 ml), sodium hydride (106 mg, 2.64 mmol) wasgradually added at room temperature and the mixture was stirred for 30minutes. N6-Ethyl-7-benzyloxy-4-chloro-6-quinolinecarboxamide (720 mg,2.11 mmol) was added, and the mixture was heated at 100° C. for 2 hourswhile stirring. Upon cooling to room temperature, the reaction solutionwas distributed between ethyl acetate and water, and the organic layerwas washed with ammonia water, water and saturated brine and dried overanhydrous sodium sulfate. The solvent was distilled off, suspended inethyl acetate and diluted with hexane, and the crystals were filteredout and blow-dried to obtain the title compound (870 mg, 1.94 mmol, 92%)as brown crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.07 (3H, t, J=7.2 Hz), 3.30 (2H, m),5.40 (2H, s), 5.43-5.49 (2H, m), 6.47 (1H, d, J=5.2 Hz), 6.91 (1H, d,J=8.8 Hz), 7.01 (1H, dd, J=2.8, 8.8 Hz), 7.24 (1H, d, J=2.8 Hz),7.34-7.39 (1H, m), 7.41-7.46 (2H, m), 7.55-7.60 (3H, m), 8.36 (1H, t,J=5.2 Hz), 8.52 (1H, s), 8.62 (1H, d, J=5.2 Hz).

Example 727N6-Ethyl-7-benzyloxy-4-(3-chloro-(4-((ethylamino)carbonyl)amino)phenoxy)-6-quinolinecarboxamide

After dissolvingN6-ethyl-4-(4-amino-3-chlorophenoxy)-7-benzyloxy-6-quinolinecarboxamide(870 mg, 1.94 mmol) and pyridine (460 mg, 5.82 mmol) indimethylformamide (10 ml), phenyl chloroformate (456 mg, 2.91 mmol) wasadded while cooling on ice, and the mixture was stirred at roomtemperature for 18 hours. The reaction solution was distributed betweenethyl acetate and water, the organic layer was washed with water andsaturated brine and dried over anhydrous magnesium sulfate, the dryingagent was filtered off and the filtrate was distilled off under reducedpressure. A portion of the obtained product (460 mg, 0.810 mmol) and a 2M ethylamine-tetrahydrofuran solution (4.05 ml) were stirred together indimethylformamide (5 ml) at room temperature for 30 minutes. Thereaction solution was distributed between ethyl acetate and water, theorganic layer was washed with water and saturated brine and dried overanhydrous magnesium sulfate, the drying agent was filtered off and thefiltrate was distilled off under reduced pressure. The obtained crudeproduct was suspended in ethyl acetate and diluted with hexane, and thenthe crystals were filtered out, washed with hexane and blow-dried toobtain the title compound (347 mg, 0.669 mmol, 83%) as white crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.03-1.11 (6H, m), 3.14 (2H, m), 3.30(2H, m), 5.41 (2H, s), 6.54 (1H, d, J=5.2 Hz), 7.01 (1H, m), 7.23 (1H,dd, J=2.8, 9.2 Hz), 7.34-7.40 (1H, m), 7.41-7.49 (3H, m), 7.55-7.60 (2H,m), 7.61 (1H, s), 8.07 (1H, s), 8.27 (1H, dd, J=3.2, 9.2 Hz), 8.36 (1H,t, J=5.2 Hz), 8.51 (1H, s), 8.66 (1H, d, J=5.2 Hz).

Example 728N6-Ethyl-4-(3-chloro-4-(((methylamino)carbonyl)amino)phenoxy)-7-hydroxy-6-quinolinecarboxamide

The title compound (253 mg, 0.609 mmol, 90%) was obtained as yellowcrystals fromN6-ethyl-7-benzyloxy-4-(3-chloro-(4-((methylamino)carbonyl)amino)phenoxy)-6-quinolinecarboxamide(344 mg, 0.681 mmol), by the same procedure as in Example 83.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.18 (3H, t, J=7.2 Hz), 2.68 (3H, d,J=4.4 Hz), 3.38 (2H, m), 6.42 (1H, d, J=5.2 Hz), 6.88 (1H, q, J=4.4 Hz),7.25 (1H, dd, J=2.8, 9.2 Hz), 7.31 (1H, s), 7.49 (1H, d, J=2.8 Hz), 8.13(1H, s), 8.27 (1H, d, J=9.2 Hz), 8.61 (1H, d, J=5.2 Hz), 8.89 (1H, s).

Example 729N6-Ethyl-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-hydroxy-6-quinolinecarboxamide

The title compound (247 mg, 0.576 mmol, 90%) was obtained as yellowcrystals fromN6-ethyl-7-benzyloxy-4-(3-chloro-(4-((ethylamino)carbonyl)amino)phenoxy)-6-quinolinecarboxamide(332 mg, 0.640 mmol), by the same procedure as in Example 83.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.08 (3H, t, J=7.2 Hz), 1.18 (3H, t,J=7.2 Hz), 3.14 (2H, m), 3.39 (2H, m), 6.42 (1H, d, J=5.2 Hz), 7.00 (1H,t, J=5.2 Hz), 7.25 (1H, dd, J=2.8, 9.2 Hz), 7.30 (1H, s), 7.49 (1H, d,J=2.8 Hz), 8.08 (1H, s), 8.29 (1H, d, J=9.2 Hz), 8.61 (1H, d, J=5.2 Hz),8.90 (1H, s).

Example 730N6-Ethyl-4-(3-chloro-4-(((methylamino)carbonyl)amino)phenoxy)-7-((1-methyl-4-piperidyl)methoxy)-6-quinolinecarboxamide

N6-Ethyl-4-(3-chloro-4-(((methylamino)carbonyl)amino)phenoxy)-7-hydroxy-6-quinolinecarboxamide)(80.0 mg, 0.193 mmol), tert-butyl4-(bromomethyl)-1-piperidinecarboxylate (80.5 mg, 0.289 mmol) andpotassium carbonate (33.3 mg, 0.241 mmol) were heated and stirred indimethylformamide (1 ml) at 60° C. for 15 hours. The reaction solutionwas distributed between ethyl acetate and water, the organic layer waswashed with water and saturated brine and dried over anhydrous magnesiumsulfate, the drying agent was filtered off and the filtrate wasdistilled off under reduced pressure. The obtained product was stirredin trifluoroacetic acid (1 ml) at room temperature for 1 hour, and thenthe reaction solution was concentrated under reduced pressure, theresidue was dissolved in methanol and triethylamine was added dropwisefor neutralization. After distilling off the solvent, the residue wasdissolved in a tetrahydrofuran (2 ml)-methanol (2 ml) mixed solvent, andthen a 37% formaldehyde aqueous solution (0.360 ml), acetic acid (0.070ml) and sodium cyanoborohydride (36.3 mg, 0.579 mmol) were added in thatorder at room temperature and the mixture was stirred for 15 minutes.After adding basic silica gel to the reaction solution and concentratingit, it was subjected to silica gel column chromatography, the targetfraction was concentrated under reduced pressure, the obtained crudeproduct was suspended in ethyl acetate, the suspension was diluted withhexane, and the crystals were filtered out, washed with hexane andblow-dried to obtain the title compound (57.5 mg, 0.109 mmol, 57%) aswhite crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.16 (3H, t, J=7.2 Hz), 1.38 (2H, m),1.72-1.92 (5H, m), 2.17 (3H, s), 2.68 (3H, d, J=4.4 Hz), 2.81 (2H, m),3.36 (2H, m), 4.11 (2H, d, J=6.0 Hz), 6.53 (1H, d, J=5.2 Hz), 6.87 (1H,m), 7.22 (1H, dd, J=2.8, 8.8 Hz), 7.46 (1H, d, J=2.8 Hz), 7.49 (1H, s),8.12 (1H, s), 8.20-8.28 (2H, m), 8.50 (1H, s), 8.65 (1H, d, J=5.2 Hz).

Example 731N6-Ethyl-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-((1-methyl-4-piperidyl)methoxy)-6-quinolinecarboxamide

N6-Ethyl-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-hydroxy-6-quinolinecarboxamide(78.0 mg, 0.182 mmol), tert-butyl4-(bromomethyl)-1-piperidinecarboxylate (75.9 mg, 0.273 mmol) andpotassium carbonate (31.4 mg, 0.228 mmol) were heated and stirred indimethylformamide (1 ml) at 60° C. for 15 hours. The reaction solutionwas distributed between ethyl acetate and water, the organic layer waswashed with water and saturated brine and dried over anhydrous magnesiumsulfate, the drying agent was filtered off and the filtrate wasdistilled off under reduced pressure. The obtained product was stirredin trifluoroacetic acid (1 ml) at room temperature for 1 hour, and thenthe reaction solution was concentrated under reduced pressure, theresidue was dissolved in methanol and triethylamine was added dropwisefor neutralization. After distilling off the solvent, the residue wasdissolved in a tetrahydrofuran (2 ml)-methanol (2 ml) mixed solvent, andthen a 37% formaldehyde aqueous solution (0.340 ml), acetic acid (0.070ml) and sodium cyanoborohydride (34.3 mg, 0.546 mmol) were added in thatorder at room temperature and the mixture was stirred for 15 minutes.After adding basic silica gel to the reaction solution and concentratingit, it was subjected to silica gel column chromatography, the targetfraction was concentrated under reduced pressure, the obtained crudeproduct was suspended in ethyl acetate, the suspension was diluted withhexane, and the crystals were filtered out, washed with hexane andblow-dried to obtain the title compound (58.1 mg, 0.108 mmol, 59%) aswhite crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.08 (3H, t, J=7.2 Hz), 1.16 (3H, t,J=7.2 Hz), 1.38 (2H, m), 1.72-1.92 (5H, m), 2.17 (3H, s), 2.81 (2H, m),3.14 (2H, m), 3.35 (2H, m), 4.10 (2H, d, J=6.0 Hz), 6.53 (1H, d, J=5.2Hz), 7.00 (1H, m), 7.22 (1H, dd, J=2.8, 8.8 Hz), 7.47 (1H, d, J=2.8 Hz),7.49 (1H, s), 8.07 (1H, s), 8.22-8.29 (2H, m), 8.50 (1H, s), 8.66 (1H,d, J=5.2 Hz).

Example 732N6-Methoxy-7-benzyloxy-4-(3-chloro-(4-((ethylamino)carbonyl)amino)phenoxy)-6-quinolinecarboxamide

N6-Methoxy-4-(4-amino-3-chlorophenoxy)-7-benzyloxy-6-quinolinecarboxamide(81.0 mg, 0.180 mmol) and pyridine (32.0 mg, 0.404 mmol) were dissolvedin dimethylformamide (2 ml), and after adding phenyl chloroformate (42.3mg, 0.270 mmol) while cooling on ice, the mixture was stirred at roomtemperature for 30 minutes. A 2 M ethylamine-tetrahydrofuran solution(0.270 ml) was added to the reaction solution, and the mixture wasfurther stirred at room temperature for 30 minutes. The reactionsolution was distributed between ethyl acetate and water, the organiclayer was washed with water and saturated brine and dried over anhydrousmagnesium sulfate, the drying agent was filtered off and the filtratewas distilled off under reduced pressure. The obtained crude product wassuspended in diethyl ether and diluted with hexane, and then thecrystals were filtered out, washed with hexane and blow-dried to obtainthe title compound (68.5 mg, 0.131 mmol, 73%) as white crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.08 (3H, t, J=7.2 Hz), 3.15 (2H, m),3.72 (3H, s), 5.40 (2H, s), 6.54 (1H, d, J=5.2 Hz), 7.01 (1H, m), 7.22(1H, dd, J=2.8, 9.2 Hz), 7.32-7.37 (1H, m), 7.40-7.46 (2H, m), 7.47 (1H,d, J=2.8 Hz), 7.53-7.60 (3H, m), 8.07 (1H, s), 8.27 (1H, dd, J=3.2, 9.2Hz), 8.34 (1H, s), 8.65 (1H, d, J=5.2 Hz), 11.53 (1H, br s).

The starting materials were synthesized in the following manner.

Production Example 732-1N6-Methoxy-7-benzyloxy-4-chloro-6-quinolinecarboxamide

After adding thionyl chloride (10 ml) and a catalytic amount ofdimethylformamide to phenyl7-benzyloxy-4-oxo-1,4-dihydro-6-quinolinecarboxylate (2.32 g, 6.25mmol), the mixture was heated to reflux for 2 hours while stirring. Thereaction solution was concentrated under reduced pressure andazeotropically distilled twice with toluene, the residue was dissolvedin a dimethylformamide (20 ml) and triethylamine (20 ml) mixed solvent,methoxylamine hydrochloride (10.4 g, 125 mmol) was added thereto whilecooling in an ice water bath, and the mixture was stirred at roomtemperature for 18 hours. The reaction solution was distributed betweenethyl acetate and water, and then the organic layer was washed withwater and saturated brine and dried over anhydrous magnesium sulfate.After distilling off the solvent, it was subjected to silica gel columnchromatography, the target fraction was concentrated under reducedpressure, the obtained crude product was suspended in ethyl acetate, thesuspension was diluted with hexane, and the crystals were filtered out,washed with hexane and blow-dried to obtain the title compound (392 mg,1.14 mmol, 18%) as white crystals.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.72 (3H, s), 5.41 (2H, s), 7.32-7.38(1H, m), 7.40-7.46 (2H, m), 7.52-7.56 (2H, m), 7.64-7.70 (2H, m), 8.22(1H, s), 8.82 (1H, d, J=4.8 Hz), 11.60 (1H, br s).

Production Example 732-2N6-Methoxy-4-(4-amino-3-chlorophenoxy)-7-benzyloxy-6-quinolinecarboxamide

After dissolving 4-amino-3-chlorophenol (408 mg, 2.84 mmol) indimethylsulfoxide (10 ml), sodium hydride (114 mg, 2.84 mmol) wasgradually added at room temperature and the mixture was stirred for 30minutes. N6-Methoxy-7-benzyloxy-4-chloro-6-quinolinecarboxamide (388 mg,1.14 mmol) was added, and the mixture was heated at 100° C. for 18 hourswhile stirring. Upon cooling to room temperature, the reaction solutionwas distributed between ethyl acetate and water, and the organic layerwas washed with water and saturated brine and dried over anhydrousmagnesium sulfate. After distilling off the solvent, it was subjected tosilica gel column chromatography, the target fraction was concentratedunder reduced pressure, the obtained crude product was suspended inethyl acetate, the suspension was diluted with hexane, and the crystalswere filtered out, washed with hexane and blow-dried to obtain the titlecompound (81.0 mg, 0.180 mmol, 16%) as light red crystals.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 3.81 (3H, s), 4.22 (2H, br s), 5.43(2H, s), 6.68 (1H, d, J=6.2 Hz), 6.88 (1H, d, J=8.8 Hz), 6.94 (1H, dd,J=2.8, 8.8 Hz), 7.16 (1H, d, J=2.8 Hz), 7.41-7.58 (5H, m), 8.14 (1H, s),8.66 (1H, d, J=6.2 Hz), 9.35 (1H, s), 10.19 (1H, s).

Example 733N6-Methoxy-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-hydroxy-6-quinolinecarboxamide

The title compound (43.3 mg, 0.101 mmol, 77%) was obtained as yellowcrystals fromN6-methoxy-7-benzyloxy-4-(3-chloro-(4-((ethylamino)carbonyl)amino)phenoxy)-6-quinolinecarboxamide)(68.3 mg, 0.131 mmol), by the same procedure as in Example 83.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.08 (3H, t, J=7.2 Hz), 3.14 (2H, m),3.76 (3H, s), 6.43 (1H, d, J=5.2 Hz), 7.00 (1H, t, J=5.2 Hz), 7.25 (1H,dd, J=2.8, 9.2 Hz), 7.34 (1H, brs), 7.48 (1H, d, J=2.8 Hz), 8.07 (1H,s), 8.27 (1H, d, J=9.2 Hz), 8.60 (1H, d, J=5.2 Hz), 8.64 (1H, s).

Example 734N6-Methyl-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxamide

The target substance was obtained using a methylamine-containingmethanol solution, in the same manner as Example 249.

¹H-NMR (DMSO-d₆) δ (ppm): 0.38-0.44 (2H, m), 2.62-2.68 (2H, m),2.50-2.60 (1H, m), 2.85 (3H, d, J=4.8 Hz), 3.37 (3H, s), 3.79 (2H, t,J=4.4 Hz), 4.39 (2H, t, J=4.4 Hz), 6.52 (1H, d, J=5.2 Hz), 7.18 (1H, d,J=2.4 Hz), 7.23 (1H, dd, J=8.8 Hz, 2.4 Hz), 7.48 (1H, d, J=2.4 Hz), 7.55(1H, s), 7.96 (1H, s), 8.26 (1H, d, J=8.8 Hz), 8.35 (1H, q, J=4.8 Hz),8.65 (1H, d, J=5.2 Hz), 8.66 (1H, s).

Example 735N6-Ethyl-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxamide

The target substance was obtained using an ethylamine-containingtetrahydrofuran solution, in the same manner as Example 249.

¹H-NMR (DMSO-d₆) δ (ppm): 0.38-0.44 (2H, m), 2.62-2.68 (2H, m), 1.15(3H, t, J=7.2 Hz), 2.50-2.60 (1H, m), 3.27-3.40 (2H, m), 3.36 (3H, s),3.79 (2H, t, J=4.4 Hz), 4.39 (2H, t, J=4.4 Hz), 6.51 (1H, d, J=5.6 Hz),7.18 (1H, d, J=2.8 Hz), 7.23 (1H, dd, J=8.8 Hz, 2.8 Hz), 7.48 (1H, d,J=2.8 Hz), 7.54 (1H, s), 7.96 (1H, s), 8.26 (1H, d, J=8.8 Hz), 8.34 (1H,t, J=4.8 Hz), 8.65 (1H, d, J=5.6 Hz), 8.68 (1H, s).

Example 736N-(2-Chloro-4-(6-cyano-7-(3-(1-piperidino)propoxy)-4-quinolyl)oxyphenyl)-N′-cyclopropylurea

The title compound (102.2 mg, 0.197 mmol, 12.3%) was obtained as lightyellow crystals fromN-(4-(6-cyano-7-hydroxy-4-quinolyl)oxy-2-chlorophenyl)-N′-cyclopropylurea(500 mg, 1.60 mmol) and 1-(3-chloropropyl)piperidine hydrochloride, bythe same procedure as in Example 7.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.42 (2H, m), 0.65 (2H, m), 1.37 (2H,m), 1.48 (2H, m), 1.96 (2H, m), 2.34 (4H, m), 2.43-2.49 (4H, m), 2.56(1H, m), 4.31 (2H, m), 6.57 (1H, d, J=5.2 Hz), 7.19 (1H, d, J=2.8 Hz),7.25 (1H, dd, J=2.8, 8.8 Hz), 7.49 (1H, d, J=2.8 Hz), 7.59 (1H, s), 7.98(1H, s), 8.27 (1H, d, J=8.8 Hz), 8.71-8.74 (2H, m).

Example 737N-(3-Fluorophenyl)-N′-(4-(thieno[2,3-d]pyrimidin-4-yloxy)phenyl)urea

After adding 370 mg of iron powder, 750 mg of ammonium chloride, 30 mlof ethanol and 3 ml of water to 250 mg of4-(4-nitrophenoxy)thieno[2,3-d]pyrimidine, the mixture was stirred at80-85° C. for 2.5 hours. After returning the mixture to roomtemperature, tetrahydrofuran was added, the mixture was filtered withcelite, and ethyl acetate and water were added to the filtrate forliquid separation and extraction. The organic layer was washed withsaturated brine, dried over anhydrous sodium sulfate, filtered with plugcotton and concentrated to dryness to obtain 182 mg of an aminocompound. A 70 mg portion of this compound was refluxed to dissolutionin 4 ml of toluene and 4 ml of acetonitrile, and after adding3-fluorophenylisocyanate (90 μl), the mixture was stirred for 1 hour.Upon returning the mixture to room temperature, the precipitatedcrystals were filtered out and dried to obtain 73 mg of the titlecompound.

¹H-NMR Spectrum: (DMSOd₆) 6.72-6.80 (1H, m), 7.12 (1H, d, J=7.7 Hz),7.22 (2H, d, J=7.7 Hz), 7.28 (1H, dd, J=14.2 Hz, 7.1 Hz), 7.49 (1H, d,J=14.2 Hz), 7.52 (2H, d, J=7.7 Hz) 7.64 (1H, dd, J=6.5 Hz, 1.5 Hz), 7.84(1H, d, J=6.5 Hz), 8.60 (1H, s,), 9.00 (1H, s,), 9.10 (1H, s)

The intermediate was synthesized in the following manner.

Production Example 737-1 4-(4-Nitrophenoxy)thieno[2,3-d]pyrimidine

After adding 600 mg of 4-nitrophenol, 1.2 g of potassium carbonate and 2ml of dimethylformamide to 302 mg of the 4-chlorothieno[2,3-d]pyrimidinedescribed in Seans Acad. Sci., Ser, C (1967) 264(2)207, and stirring themixture for 30 hours at 130° C., the mixture was returned to roomtemperature, water was added, liquid separation and extraction wereperformed with an ethyl acetate-tetrahydrofuran mixed solvent, and thesolid obtained by concentration to dryness was washed with ether toobtain 250 mg of the title compound.

¹H-NMR Spectrum: (DMSOd₆) 7.63 (2H, d, J=8.7 Hz), 7.68 (1H, d, J=6.1Hz), 8.00 (1H, d, J=6.1 Hz), 8.35 (2H, d, J=8.7 Hz), 8.65 (1H, s,)

Example 738N-(4-Fluorophenyl)-N′-(4-(thieno[2,3-d]pyrimidin-4-yloxy)phenyl)urea

The title compound (92 mg) was obtained from 90 mg of the amino compounddescribed in Example 737, using 4-fluorophenyl isocyanate (90 μl), bythe same procedure as in Example 737.

¹H-NMR Spectrum: (DMSOd₆) 7.12 (2H, t, J=9.6 Hz), 7.20 (2H, d, J=8.6Hz), 7.46 (2H, dd, J=9.6 Hz, 5.2 Hz), 7.52 (2H, d, J=8.6 Hz), 7.63 (1H,d, J=6.2 Hz), 7.94 (1H, d, J=6.2 Hz), 8.59 (1H, s), 8.89 (1H, s), 8.94(1H, s)

Example 739N-(3-Fluorophenyl)-N′-(4-(thieno[3,2-d]pyrimidin-4-yloxy)phenyl)urea

An amino compound (310 mg) was obtained from4-(4-nitrophenoxy)thieno[3,2-d]pyrimidine (375 mg) by the methoddescribed in Example 737. The title compound (250 mg) was obtained from135 mg of the amino compound using 3-fluorophenyl isocyanate (90 μl), bythe method described in Example 737.

¹H-NMR Spectrum: (DMSOd₆) 6.72-7.56 (8H, m), 7.65 (1H, d, J=6.2 Hz),8.44 (1H, d, J=6.2 Hz), 8.68 (1H, s,), 8.86 (1H, s,), 8.95 (1H, s)

The intermediate was synthesized in the following manner.

Production Example 739-1 4-(4-Nitrophenoxy)thieno[3,2-d]pyrimidine

The title compound (382 mg) was obtained from 315 mg of the4-chlorothieno[3,2-d]pyrimidine described in Seans Acad. Sci., Ser, C(1967) 264(1)100, by the method described in Production Example 737-1.

¹H-NMR Spectrum: (DMSOd₆) 7.63-7.69 (2H, m), 7.70 (1H, d, J=6.1 Hz),8.32-8.38 (2H, m), 8.51 (1H, d, J=6.1 Hz), 8.73 (1H, s,)

Example 740N-(4-Fluorophenyl)-N′-(4-(thieno[3,2-d]pyrimidin-4-yloxy)phenyl)urea

The title compound (135 mg) was obtained from 150 mg of the aminocompound described in Example 739 using 4-fluorophenyl isocyanate (94μl), by the same procedure as in Example 737.

¹H-NMR Spectrum: (DMSOd₆) 7.00-7.56 (8H, m), 7.65 (1H, d, J=6.1 Hz),8.44 (1H, d, J=6.1 Hz), 8.67 (1H, s), 8.73 (1H, s), 8.78 (1H, s)

Example 741N-(4-(6,7-Dimethoxyquinolin-4-yloxy)phenyl)-N′-(3-methanesulfonylphenyl)urea

The 4-(6,7-dimethoxyquinolin-4-yloxy)phenylamine (296 mg, 1.00 mmol)obtained by the method described in WO97/17329 and(3-methanesulfonylphenyl)carbamic acid phenyl ester (291 mg, 1.00 mmol)were heated and stirred in dimethylsulfoxide (3 ml) at 85° C. for 2hours. The reaction solution was distributed between ethyl acetate andwater, the organic layer was washed with 1N aqueous sodium hydroxide,water and saturated brine and dried over anhydrous magnesium sulfate,the drying agent was filtered off and the filtrate was distilled offunder reduced pressure. The obtained crude product was subjected tosilica gel column chromatography (eluent-ethyl acetate:methanol=30:1),the fraction containing the target substance was concentrated andsuspended in ethyl acetate, the suspension was diluted with hexane andthe crystals were filtered out, washed with hexane and blow-dried toobtain the title compound (430 mg, 0.871 mmol, 87%) as colorlesscrystals.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 3.16 (3H, s), 4.03 (3H, s), 4.05 (3H,s), 6.46 (1H, d, J=5.2 Hz), 7.12-7.18 (2H, m), 7.41 (1H, s), 7.50-7.62(6H, m), 7.81 (1H, s), 7.93 (1H, s), 8.11-8.15 (1H, m), 8.48 (1H, d,J=5.2 Hz).

Example 742N-(2-Chloro-4-((6-cyano-7-(4-piperidylmethoxy)-4-quinolyl)oxy)phenyl)-N′-methylurea

N-(2-chloro-4-(6-cyano-7-hydroxyquinolin-4-yloxy)phenyl)-N′-methylurea(125 mg) was added to dimethylformamide (1.5 ml), and then tert-butyl4-(bromomethyl)-1-piperidinecarboxylate (141 mg) and potassium carbonate(93 mg) were added thereto and the mixture was heated at 60° C. for 3hours. Water was added to the reaction solution, extraction wasperformed with ethyl acetate, the organic layer was washed with waterand saturated brine in that order and dried over anhydrous sodiumsulfate, and the solvent was distilled off under reduced pressure. Theobtained crude product was recrystallized with ethyl acetate to obtaintert-butyl4-(((4-(3-chloro-4-((methylamino)carbonyl)aminophenoxy)-6-cyano-7-quinolyl)oxy)methyl)-1-piperidinecarboxylate(21 mg) as light yellow crystals. These were dissolved intrifluoroacetic acid (1.0 ml), and the solution was stirred for 10minutes at room temperature. Water (2 ml) was added, the mixture wasneutralized with sodium bicarbonate, and the precipitated crystals werefiltered out to obtain the title compound (16 mg).

H-NMR (DMSO-d₆) δ (ppm): 1.20-1.35 (4H, m), 1.70-1.80 (2H, m), 1.90-2.01(1H, m), 2.66 (3H, d, J=4.4 Hz), 2.95-3.05 (2H, m), 4.12 (2H, d, J=6.0Hz), 6.58 (1H, d, J=5.2 Hz), 6.84-6.92 (1H, m), 7.21-7.26 (1H, m), 7.48(1H, d, J=2.4 Hz), 7.59 (1H, s), 8.12 (1H, s), 8.22-8.28 (1H, m),8.71-8.78 (2H, m).

Example 743N-(2-Chloro-4-((6-cyano-7-((1-methyl-4-piperidyl)methoxy)-4-quinolyl)oxy)phenyl)-N′-methylurea

After dissolvingN-(2-chloro-4-((6-cyano-7-(4-piperidylmethoxy)-4-quinolyl)oxy)phenyl)-N′-methylurea(15 mg) in tetrahydrofuran (0.5 ml) and methanol (0.5 ml), there wereadded 37% aqueous formaldehyde (0.03 ml), acetic acid (0.06 ml) andsodium cyanoborohydride (5.0 mg) at room temperature, and the mixturewas stirred for 1 hour. Water was added to the reaction solution,saturated aqueous sodium bicarbonate was added for neutralization, andextraction was performed with ethyl acetate. The organic layer waswashed with water and the solvent was distilled off to obtain a crudeproduct. This was recrystallized with ethyl acetate to obtain the titlecompound (10 mg) as white crystals.

H-NMR (DMSO-d₆) δ (ppm): 1.13-1.47 (2H, m), 1.75-1.95 (5H, m), 2.17 (3H,s), 2.68 (3H, s), 2.78-2.87 (2H, m), 4.17 (2H, d, J=6.0 Hz), 6.59 (1H,d, J=5.2 Hz), 6.95 (1H, brs), 7.22-7.28 (1H, m), 7.48 (1H, d, J=2.4 Hz),7.61 (1H, s), 8.18 (1H, brs), 8.22-8.29 (1H, m), 8.72-8.77 (2H, m).

The structural formulas for the compounds obtained in the precedingProduction Examples and Examples are shown below in Tables 4 to 51.

TABLE 4

TABLE 5

TABLE 6

TABLE 7 pro. ex. 182-3

pro. ex. 182-4

pro. ex. 183-1

pro. ex. 183-2

pro. ex. 184-1

pro. ex. 184-2

pro. ex. 185-1

pro. ex. 185-2

pro. ex. 185-3

pro. ex. 186-1

pro. ex. 186-2

pro. ex. 186-3

pro. ex. 190-1

pro. ex. 192-1

pro. ex. 193-1

pro. ex. 195-1

pro. ex. 197-1

pro. ex. 197-2

pro. ex. 197-3

pro. ex. 199-1

pro. ex. 199-2

TABLE 8 pro. ex. 199-3

pro. ex. 200-1

pro. ex. 201-1

pro. ex. 203-1

pro. ex. 203-2

pro. ex. 204-1

pro. ex. 205-1

pro. ex. 205-2

pro. ex. 205-3

pro. ex. 206-1

pro. ex. 206-2

pro. ex. 207-1

pro. ex. 207-2

pro. ex. 208-1

pro. ex. 209-1

pro. ex. 209-2

pro. ex. 210-1

pro. ex. 210-2

pro. ex. 211-1

pro. ex. 211-2

pro. ex. 215-1

TABLE 9 pro. ex. 216-1

pro. ex. 217-1

pro. ex. 217-2

pro. ex. 219-1

pro. ex. 219-2

pro. ex. 222-1

pro. ex. 222-2

pro. ex. 222-3

pro. ex. 222-4

pro. ex. 224-1

pro. ex. 226-1

pro. ex. 226-2

pro. ex. 226-3

pro. ex. 232-1

pro. ex. 235-1

pro. ex. 235-2

pro. ex. 244-1

pro. ex. 244-2

pro. ex. 247-1

pro. ex. 247-2

pro. ex. 247-3

TABLE 10 pro. ex. 247-4

pro. ex. 247-5

pro. ex. 248-1

pro. ex. 248-2

pro. ex. 248-3

pro. ex. 249-1

pro. ex. 249-2

pro. ex. 249-3

pro. ex. 249-4

pro. ex. 249-5

pro. ex. 252-1

pro. ex. 252-2

pro. ex. 252-3

pro. ex. 262-1

pro. ex. 263-1

pro. ex. 263-2

pro. ex. 263-3

pro. ex. 267-1

pro. ex. 267-2

pro. ex. 276-1

pro. ex. 276-2

TABLE 11 pro. ex. 277-1

pro. ex. 277-2

pro. ex. 280-1

pro. ex. 280-2

pro. ex. 284-1

pro. ex. 287-1

pro. ex. 301-1

pro. ex. 302-2

pro. ex. 302-3

pro. ex. 303-1

pro. ex. 305-1

pro. ex. 307-1

pro. ex. 310-1

pro. ex. 311-1

pro. ex. 313-1

pro. ex. 314-1

pro. ex. 316-1

pro. ex. 318-1

pro. ex. 320-1

pro. ex. 322-1

pro. ex. 323-1

TABLE 12 pro. ex. 324-1

pro. ex. 325-1

pro. ex. 326-1

pro. ex. 327-1

pro. ex. 328-1

pro. ex. 329-1

pro. ex. 335-1

pro. ex. 339-1

pro. ex. 339-2

pro. ex. 347-1

pro. ex. 348-1

pro. ex. 350-1

pro. ex. 353-1

pro. ex. 360-1

pro. ex. 360-2

pro. ex. 363-1

pro. ex. 363-2

pro. ex. 366-1

pro. ex. 368-1

pro. ex. 370-1

pro. ex. 370-2

TABLE 13 pro. ex. 379-1

pro. ex. 379-2

pro. ex. 379-3

pro. ex. 395-1

pro. ex. 395-2

pro. ex. 425-1

pro. ex. 426-1

pro. ex. 429-1

pro. ex. 429-2

pro. ex. 430-1

pro. ex. 430-2

pro. ex. 431-1

pro. ex. 432-1

pro. ex. 433-1

pro. ex. 457-1

pro. ex. 457-2

pro. ex. 457-3

pro. ex. 457-4

pro. ex. 457-5

pro. ex. 458-1

pro. ex. 458-2

TABLE 14 pro. ex. 458-3

pro. ex. 461-1

pro. ex. 462-1

pro. ex. 462-2

pro. ex. 462-3

pro. ex. 467-1

pro. ex. 467-2

pro. ex. 467-3

pro. ex. 468-1

pro. ex. 468-2

pro. ex. 468-3

pro. ex. 474-1

pro. ex. 475-1

pro. ex. 475-2

pro. ex. 475-3

pro. ex. 476-1

pro. ex. 476-2

pro. ex. 476-3

pro. ex. 478-1

pro. ex. 478-2

pro. ex. 478-3

pro. ex. 482-1

pro. ex. 484-1

pro. ex. 488-1

TABLE 15 pro. ex. 488-2

pro. ex. 488-3

pro. ex. 489-1

pro. ex. 489-2

pro. ex. 489-3

pro. ex. 490-1

pro. ex. 490-2

pro. ex. 491-1

pro. ex. 491-2

pro. ex. 492-1

pro. ex. 492-2

pro. ex. 495-1

pro. ex. 497-1

pro. ex. 497-2

pro. ex. 500-1

pro. ex. 501-1

pro. ex. 501-2

pro. ex. 503-1

pro. ex. 505-1

pro. ex. 506-1

pro. ex. 506-2

pro. ex. 506-3

pro. ex. 506-4

TABLE 16 pro. ex. 510-1

pro. ex. 510-2

pro. ex. 510-22

pro. ex. 510-3

pro. ex. 510-4

pro. ex. 512-1

pro. ex. 512-2

pro. ex. 512-3

pro. ex. 513-1

pro. ex. 530-1

pro. ex. 530-2

pro. ex. 532-1

pro. ex. 533-1

pro. ex. 534-1

pro. ex. 534-2

pro. ex. 534-3

pro. ex. 534-4

pro. ex. 537-1

pro. ex. 537-2

pro. ex. 537-3

pro. ex. 538-1

pro. ex. 538-2

pro. ex. 538-3

pro. ex. 538-4

TABLE 17 pro. ex. 551-1

pro. ex. 551-2

pro. ex. 551-3

pro. ex. 557-1

pro. ex. 557-2

pro. ex. 561-1

pro. ex. 568-1

pro. ex. 568-2

pro. ex. 574-1

pro. ex. 574-2

pro. ex. 591-1

pro. ex. 593-1

pro. ex. 616-1

pro. ex. 616-2

pro. ex. 616-3

pro. ex. 618-1

pro. ex. 618-2

pro. ex. 618-3

pro. ex. 618-4

pro. ex. 618-5

pro. ex. 618-6

pro. ex. 625-1

pro. ex. 626-1

pro. ex. 645-1

TABLE 18 pro. ex. 645-2

pro. ex. 645-3

pro. ex. 645-4

pro. ex. 645-5

pro. ex. 657-1

pro. ex. 657-2

pro. ex. 657-3

pro. ex. 657-4

pro. ex. 657-5

pro. ex. 658-1

pro. ex. 659-1

pro. ex. 670-1-1

pro. ex. 670-1-2

pro. ex. 670-1-3

pro. ex. 670-1-4

pro. ex. 671-1

pro. ex. 671-2

pro. ex. 671-3

TABLE 19 pro. ex. 713-1

pro. ex. 713-2

pro. ex. 713-3

pro. ex. 715-1

pro. ex. 720-1

pro. ex. 720-2

pro. ex. 723-1

pro. ex. 726-1

pro. ex. 726-2

pro. ex. 732-1

pro. ex. 732-2

pro. ex. 737-1

pro. ex. 739-1

TABLE 20 ex. 1

ex. 2

ex. 3

ex. 4-A

ex. 4-B

ex. 5-A

ex. 5-B

ex. 6-A

ex. 6-B

ex. 7

ex. 8

ex. 9

ex. 10

ex. 11

ex. 12

ex. 13

ex. 14

ex. 15

ex. 16

ex. 17

ex. 18

ex. 19

ex. 20

ex. 21

TABLE 21 ex. 22

ex. 23

ex. 24

ex. 25

ex. 26

ex. 27

ex. 28

ex. 29

ex. 30

ex. 31

ex. 32

ex. 33

ex. 34

ex. 35

ex. 36

ex. 37

ex. 38

ex. 39

ex. 40

ex. 41

ex. 42

ex. 43

ex. 44

ex. 45

TABLE 22 ex. 46

ex. 47

ex. 48

ex. 49

ex. 50

ex. 51

ex. 52

ex. 53

ex. 54

ex. 55

ex. 56

ex. 57

ex. 58

ex. 59

ex. 60

ex. 61

ex. 62

ex. 63

ex. 64

ex. 65

ex. 66

ex. 67

ex. 68

ex. 69

TABLE 23 ex. 70

ex. 71

ex. 72

ex. 73

ex. 74

ex. 75

ex. 76

ex. 77

ex. 78

ex. 79

ex. 80

ex. 81

ex. 82

ex. 83

ex. 84

ex. 85

ex. 86

ex. 87

ex. 88

ex. 89

ex. 90

ex. 91

ex. 92

ex. 93

TABLE 24 ex. 94 

ex. 95 

ex. 96 

ex. 97 

ex. 98 

ex. 99 

ex. 100

ex. 101-B

ex. 101-A

ex. 102

ex. 103

ex. 104

ex. 105

ex. 106

ex. 107

ex. 108

ex. 109

ex. 110

ex. 111

ex. 112

ex. 113

ex. 114

ex. 115

ex. 116

TABLE 25 ex. 117

ex. 118

ex. 119

ex. 120

ex. 121

ex. 122

ex. 123

ex. 124

ex. 125

ex. 126

ex. 127

ex. 128

ex. 129

ex. 130

ex. 131

ex. 132

ex. 133

ex. 134

ex. 135

ex. 136

ex. 137

ex. 138

ex. 139

ex. 140

TABLE 26 ex. 141

ex. 142

ex. 143

ex. 144

ex. 145

ex. 146

ex. 147

ex. 148

ex. 149

ex. 150

ex. 151

ex. 152

ex. 153

ex. 154

ex. 155

ex. 156

ex. 157

ex. 158

ex. 159

ex. 160

ex. 161

ex. 162

ex. 163

ex. 164

TABLE 27 ex. 165

ex. 166

ex. 167

ex. 168

ex. 169

ex. 170

ex. 171

ex. 172

ex. 173

ex. 174

ex. 175

ex. 176

ex. 177

ex. 178

ex. 179

ex. 180

ex. 181

ex. 182

ex. 183

ex. 184

ex. 185

ex. 186

ex. 187

ex. 188

TABLE 28 ex. 189

ex. 190

ex. 191

ex. 192

ex. 193

ex. 194

ex. 195

ex. 196

ex. 197

ex. 198

ex. 199

ex. 200

ex. 201

ex. 202

ex. 203

ex. 204

ex. 205

ex. 206

ex. 207

ex. 208

ex. 209

ex. 210

ex. 211

ex. 212

TABLE 29 ex. 213-A

ex. 213-B

ex. 213-C

ex. 214

ex. 215

ex. 216

ex. 217

ex. 218

ex. 219

ex. 220

ex. 221

ex. 222

ex. 223

ex. 224

ex. 225

ex. 226

ex. 227

ex. 228

ex. 229

ex. 230

ex. 231

ex. 232

ex. 233

ex. 234

TABLE 30 ex. 235

ex. 236

ex. 237

ex. 238

ex. 239

ex. 240

ex. 241

ex. 242

ex. 243

ex. 244

ex. 245

ex. 246

ex. 247

ex. 248

ex. 249

ex. 250

ex. 251

ex. 252

ex. 253

ex. 254

ex. 255

ex. 256

ex. 257

ex. 258

TABLE 31 ex. 259

ex. 260

ex. 261

ex. 262

ex. 263

ex. 264

ex. 265

ex. 266

ex. 267

ex. 268

ex. 269

ex. 270

ex. 271

ex. 272

ex. 273

ex. 274

ex. 275

ex. 276

ex. 277

ex. 278

ex. 279

ex. 280

ex. 281

ex. 282

TABLE 32 ex. 283

ex. 284

ex. 285

ex. 286

ex. 287

ex. 288

ex. 289

ex. 290

ex. 291

ex. 292

ex. 293

ex. 294

ex. 295

ex. 296

ex. 297

ex. 298

ex. 299

ex. 300

ex. 301

ex. 302

ex. 303

ex. 304

ex. 305

ex. 306

TABLE 33 ex. 307

ex. 308

ex. 309

ex. 310

ex. 311

ex. 312

ex. 313

ex. 314

ex. 315

ex. 316

ex. 317

ex. 318

ex. 319

ex. 320

ex. 321

ex. 322

ex. 323

ex. 324

ex. 325

ex. 326

ex. 327

ex. 328

ex. 329

ex. 330

TABLE 34 ex. 331-1

ex. 331-2

ex. 332

ex. 333

ex. 334

ex. 335

ex. 336

ex. 337

ex. 338

ex. 339

ex. 340

ex. 341

ex. 342

ex. 343

ex. 344

ex. 345

ex. 346

ex. 347

ex. 348

ex. 349

ex. 350

ex. 351

ex. 352

ex. 353

ex. 354

TABLE 35 ex. 355

ex. 356

ex. 357

ex. 358

ex. 359

ex. 360

ex. 361

ex. 362

ex. 363

ex. 364

ex. 365

ex. 366

ex. 367

ex. 368

ex. 369

ex. 370

ex. 371

ex. 372

ex. 373

ex. 374

ex. 375

ex. 376

ex. 377

ex. 378

TABLE 36 ex. 379

ex. 380

ex. 381

ex. 382

ex. 383

ex. 384

ex. 385

ex. 386

ex. 387

ex. 388

ex. 389

ex. 390

ex. 391-1

ex. 391-2

ex. 392

ex. 393

ex. 394

ex. 395

ex. 396

ex. 397

ex. 398

ex. 399

ex. 400

ex. 401

ex. 402

TABLE 37 ex. 403

ex. 404

ex. 405

ex. 406

ex. 407

ex. 408

ex. 409

ex. 410

ex. 411

ex. 412

ex. 413

ex. 414

ex. 415

ex. 416

ex. 417

ex. 418

ex. 419

ex. 420

ex. 421

ex. 422

ex. 423

ex. 424

ex. 425

ex. 426

TABLE 38 ex. 427

ex. 428

ex. 429

ex. 430

ex. 431

ex. 432

ex. 433

ex. 434

ex. 435

ex. 436

ex. 437

ex. 438

ex. 439

ex. 440

ex. 441

ex. 442

ex. 443

ex. 444

ex. 445

ex. 446

ex. 447

ex. 448

ex. 449

ex. 450

TABLE 39 ex. 451

ex. 452

ex. 453

ex. 454

ex. 455

ex. 456

ex. 457

ex. 458

ex. 459

ex. 460

ex. 461

ex. 462

ex. 463

ex. 464

ex. 465

ex. 466

ex. 467

ex. 468

ex. 469

ex. 470

ex. 471

ex. 472

ex. 473

ex. 474

TABLE 40 ex. 475

ex. 476

ex. 477

ex. 478

ex. 479

ex. 480

ex. 481

ex. 482

ex. 483

ex. 484

ex. 485

ex. 486

ex. 487

ex. 488

ex. 489

ex. 490

ex. 491

ex. 492

ex. 493

ex. 494

ex. 495

ex. 496

ex. 497

ex. 498

TABLE 41 ex. 499

ex. 500

ex. 501

ex. 502

ex. 503

ex. 504

ex. 505

ex. 506

ex. 507

ex. 508

ex. 509

ex. 510

ex. 511

ex. 512

ex. 513

ex. 514

ex. 515

ex. 516

ex. 517

ex. 518

ex. 519

ex. 520

ex. 521

ex. 522

TABLE 42 ex. 523

ex. 524

ex. 525

ex. 526

ex. 527

ex. 528

ex. 529

ex. 530

ex. 531

ex. 532

ex. 533

ex. 534

ex. 535

ex. 536

ex. 537

ex. 538

ex. 539

ex. 540

ex. 541

ex. 542

ex. 543

ex. 544

ex. 545

ex. 546

TABLE 43 ex. 547

ex. 548

ex. 549

ex. 550

ex. 551

ex. 552

ex. 553

ex. 554

ex. 555

ex. 556

ex. 557

ex. 558

ex. 559

ex. 560

ex. 561

ex. 562

ex. 563

ex. 564

ex. 565

ex. 566

ex. 567

ex. 568

ex. 569

ex. 570

TABLE 44 ex. 571

ex. 572

ex. 573

ex. 574

ex. 575

ex. 576

ex. 577

ex. 578

ex. 579

ex. 580

ex. 581

ex. 582

ex. 583

ex. 584

ex. 585

ex. 586

ex. 589

ex. 590

ex. 591

ex. 592

ex. 593

ex. 594

ex. 595

ex. 596

TABLE 45 ex. 597

ex. 598

ex. 599

ex. 600

ex. 601

ex. 602

ex. 603

ex. 604

ex. 605

ex. 606

ex. 607

ex. 608

ex. 609

ex. 610

ex. 611

ex. 612

ex. 613

ex. 614

ex. 615

ex. 616

ex. 617

ex. 618

ex. 619

ex. 620

TABLE 46 ex. 621

ex. 622

ex. 623

ex. 624

ex. 625

ex. 626

ex. 627

ex. 628

ex. 629

ex. 630

ex. 631

ex. 632

ex. 633

ex. 634

ex. 635

ex. 636

ex. 637

ex. 638

ex. 639

ex. 640

ex. 641

ex. 642

ex. 643

ex. 644

TABLE 47 ex. 645

ex. 646

ex. 647

ex. 648

ex. 649

ex. 650

ex. 651

ex. 652

ex. 653

ex. 654

ex. 655

ex. 656

ex. 657

ex. 658

ex. 659

ex. 660

ex. 661

ex. 662

ex. 663

ex. 664

ex. 665

ex. 666

ex. 667

ex. 668

TABLE 48 ex. 669

ex. 670

ex. 670-1

ex. 671

ex. 672

ex. 673

ex. 674

ex. 675

ex. 676

ex. 677

ex. 678

ex. 679

ex. 680

ex. 681

ex. 682

ex. 683

ex. 684

TABLE 49 ex. 697

ex. 698

ex. 699

ex. 700

ex. 701

ex. 702

ex. 703

ex. 704

ex. 705

ex. 706

ex. 707

ex. 708

ex. 709

ex. 710

ex. 711

ex. 712

ex. 713

ex. 714

ex. 715

ex. 716

TABLE 50 ex. 717

ex. 718

ex. 719

ex. 720

ex. 721

ex. 722

ex. 723

ex. 724

ex. 725

ex. 726

ex. 727

ex. 728

ex. 729

ex. 730

ex. 731

ex. 732

ex. 733

ex. 734

ex. 735

ex. 736

ex. 737

ex. 738

ex. 739

ex. 740

ex. 741

TABLE 51 ex. 742

ex. 743

pro. ex. 570-1

pro. ex. 570-2

1. A compound represented by the following general formula:

wherein R^(c13) is a hydrogen atom, cyano, a halogen atom, formyl, anoptionally substituted C₁₋₆ alkyl group, a group represented by theformula:

wherein V^(c21) is —CO— or methylene; V^(c22) and V^(c23) are eachindependently a hydrogen atom, optionally substituted C₁₋₆ alkyl group,optionally substituted C₂₋₆ alkenyl group, optionally substituted C₂₋₆alkynyl group, optionally substituted C₃₋₈ alicyclic hydrocarbon group,optionally substituted 5- to 14-membered heterocyclic group, optionallysubstituted 5- to 14-membered aromatic heterocyclic group or optionallysubstituted C₆₋₁₄ aryl group, or a group represented by the formula:—V^(c21)—O—V^(c22) wherein V^(c21) and V^(c22) have the same definitionsas above; X^(y2) is an optionally substituted group selected from thegroup consisting of the following formulas:

wherein Z¹² is a hydrogen atom, optionally substituted C₁₋₆ alkyl group,optionally substituted C₂₋₆ alkenyl group, optionally substituted C₂₋₆alkynyl group, optionally substituted C₃₋₈ alicyclic hydrocarbon group,optionally substituted C₆₋₁₄ aryl group, optionally substituted 5- to14-membered heterocyclic group, optionally substituted 5- to 14-memberedaromatic heterocyclic group or a group represented by the formula:

wherein Z³¹, Z³³ and Z³⁴ are each independently methylene, —CO—, —NH— or—O—, and Z³² is a single bond, methylene, —CO—, —NH— or —O—, and R¹ andR² are each independently a hydrogen atom, optionally substituted C₁₋₆alkyl group, optionally substituted C₂₋₆ alkenyl group, optionallysubstituted C₂₋₆ alkynyl group, optionally substituted C₃₋₈ alicyclichydrocarbon group, optionally substituted C₂₋₇ acyl group or optionallysubstituted C₂₋₇ alkoxycarbonyl group; and W¹¹ is an optionallysubstituted carbon atom or a nitrogen atom; R^(c11) is a grouprepresented by the formula —V^(c11)—V^(c12)—V^(c13), wherein V^(c11) isa single bond, oxygen atom, optionally substituted benzene ring,optionally substituted 5- to 14-membered aromatic heterocyclic group or—CO—; V^(c12) is a single bond, oxygen atom or optionally substitutedC₁₋₆ alkylene group; and V^(c13) is an optionally substituted C₁₋₆ alkylgroup, an optionally substituted C₂₋₆ alkenyl group, an optionallysubstituted C₂₋₆ alkynyl group, an optionally substituted C₃₋₈ alicyclichydrocarbon group, hydroxyl, carboxyl, an optionally substituted C₂₋₇alkoxycarbonyl group, an optionally substituted 5- to 14-memberedheterocyclic group, an optionally substituted 5- to 14-membered aromaticheterocyclic group, an optionally substituted C₆₋₁₄ aryl group, a grouprepresented by the formula —NR^(c21)R^(c22), wherein R^(c21) and R^(c22)are each independently a hydrogen atom or optionally substituted C₁₋₆alkyl group, or a hydrogen atom; and R^(c12) is a hydrogen atom,optionally substituted C₁₋₆ alkyl group or optionally substituted C₃₋₈alicyclic hydrocarbon group; with the exception of the followingcompounds (1) and (2): (1) a compound wherein R¹ and R² are hydrogenatoms and Z¹² is a C₆₋₁₄ aryl group, a 5- to 14-membered heterocyclicgroup, a C₁₋₆ alkyl group substituted with a 5- to 14-membered aromaticheterocyclic group, a 5- to 10-membered heterocyclic group or a C₅₋₁₀alicyclic hydrocarbon group, a C₂₋₆ alkenyl group substituted with a 5-to 10-membered heterocyclic group or a C₅₋₁₀ alicyclic hydrocarbongroup, a C₂₋₆ alkynyl group substituted with a 5- to 10-memberedheterocyclic group or a C₅₋₁₀ alicyclic hydrocarbon group, or a C₃₋₈alicyclic hydrocarbon group substituted with a 5- to 10-memberedheterocyclic group or a C₅₋₁₀ alicyclic hydrocarbon group; and (2) acompound wherein X^(y2) is a group represented by the formula:

wherein Z¹² is a C₆₋₁₄ aryl group, a 5- to 14-membered heterocyclicgroup, a 5- to 14-membered aromatic heterocyclic group, a C₁₋₆ alkylgroup substituted with a 5- to 10-membered heterocyclic group or a C₅₋₁₀alicyclic hydrocarbon group, a C₂₋₆ alkenyl group substituted with a 5-to 10-membered heterocyclic group or a C₅₋₁₀ alicyclic hydrocarbongroup, a C₂₋₆ alkynyl group substituted with a 5- to 10-memberedheterocyclic group or a C₅₋₁₀ alicyclic hydrocarbon group, or a C₃₋₈alicyclic hydrocarbon group, a salt thereof or a hydrate of theforegoing.
 2. A compound according to claim 1, a salt of the compound ora hydrate of the foregoing, wherein R^(c11) is a group represented bythe formula:

wherein V^(f11) is a single bond, an optionally substituted C₁₋₆alkylene group or a group represented by the formula:

and V^(f12) is a hydrogen atom, a hydroxyl group, an optionallysubstituted 5- to 14-membered heterocyclic group, an optionallysubstituted 5- to 14-membered aromatic heterocyclic group, an optionallysubstituted C₆₋₁₄ aryl group or a group represented by the formula—NR^(f21)R^(f22) wherein R^(f21) and R^(f22) are each independently ahydrogen atom or an optionally substituted C₁₋₆ alkyl group.